Substituted indole derivatives

ABSTRACT

Provided herein are indole derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

This application claims priority to U.S. Provisional Application No.60/508,592, filed Oct. 2, 2003, and U.S. Provisional Application No.60/556,599, filed Mar. 26, 2004, which are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

This invention relates to antineoplastic, anti-inflammatory andanalgesic indole derivatives, pharmaceutical compositions containingthem, methods for their use, and methods for preparing these compounds.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for thetreatment of inflammation, pain, and acute and chronic inflammatorydisorders such as osteoarthritis and rheumatoid arthritis. Thesecompounds are thought to work by inhibiting the enzyme cyclooxygenase(COX), which is also known as prostaglandin G/H synthase. COX catalyzesthe conversion of arachidonic acid to prostaglandins.

Various forms of COX enzymes have been reported. They include aconstitutive form known as COX-1, an inducible form known as COX-2 andthe recently discovered COX-3, a variant of COX-1 that is inhibited byacetaminophen. COX-2 is inducible by mitogens, endotoxin, hormones,tumor promoters and growth factors. COX-1 is responsible for endogenousrelease of prostaglandins important for maintenance of gastrointestinalintegrity and renal blood flow. Many of the side effects associated withNSAIDs are believed to be due to the inhibition of COX-1. Because ofthis, compounds that are selective for COX-2 have been developed andmarketed. However, COX-2 inhibitors have been reported to causedyspepsia, gastropathy and cardiovascular problems.

NSAIDs have also been used for cancer prevention and cancer treatment.The mechanism by which NSAIDs work in cancer treatment and cancerprevention may be related to COX overexpression. For example, somestudies appear to indicate a link between COX expression andcarcinogenesis. For example, cell lines that overexpress COX-2 arereported to be resistant to apoptosis, have increased invasiveness, andincreased angiogenesis potential. Further, studies indicate thatincreased amounts of prostaglandins and COX-2 are commonly found inpremalignant tissues and malignant tumors. Researchers have reportedthat COX-2 is up-regulated in several types of human cancers, includingcolon, pancreatic and breast.

Other studies report that the chemoprotective and antineoplasticproperties of NSAIDs may occur in a COX-independent mechanism. Forexample, R-flurbiprofen is chemoprotective in the mouse model ofintestinal polyposis and prostate cancer even though it does not haveCOX inhibitory activity. Similarly, sulindac sulfone, a metabolite ofthe NSAID sulindac, inhibits azoxy-methane-induced colon tumors in ratseven though it does not have COX inhibitory activity. Further, NSAIDscan induce apoptosis in cancer cells that do not express COX-2 (Baek etal. 2001 Mol. Pharmacol. 59:901-908). The authors of these studiesreport that the chemoprotective and antineoplastic effects of NSAIDsoccur via COX-dependent and COX-independent mechanisms.

β-catenin (also known as cadherin-associated protein) is a protooncogenein the downstream pathway of the wingless/frizzled (wnt/fzd) signalingpathway. Alterations in the pathways involved in regulating β-cateninare associated in the pathogenesis of many human cancers, includingcolorectal, desmoid (aggressive fibromatosis), endometrial,hepatocellular, leukemias, kidney, medulloblastoma, melanoma, ovarian,pancreatic, prostate, thyroid and uterine (Polakis, 2000 Genes Dev.14:1837-1851; Chung et al. 2002 Blood 100:982-990).

β-catenin is reported to exist in at least three forms: membrane-bound(adherens complex), cytosolic, and nuclear. The nuclear accumulation ofβ-catenin, in concert with TCF/LEF proteins, induces downstream genes,including many genes implicated in tumorigenesis, for example, cyclinD1, and c-myc. The literature also reports that β-catenin is involved inthe gene regulation of the androgen receptor, providing evidence for arole for the Wnt/β-catenin-TCF pathway for normal and neoplasticprostate growth (Amir et al., 2003, J. Biol. Chem. 278:30828-30834). Theliterature also reports that β-catenin may up-regulate COX-2 (Okamura etal., 2003, Cancer Res. 63:728-34).

β-catenin levels are reported to be regulated posttranslationally by theWnt/fzd signaling pathway. In the absence of a Wnt signal, any β-cateninnot bound to adherins is marked for degradation by a complex of proteinsbound to β-catenin that includes glycogen synthase kinase-3β (GSK-3β),adenomatous polyposis coli (APC) protein, and axin. This complexfacilitates the phosphorylation of β-catenin by GSK-3β and subsequentrapid degradation of β-catenin through proteasome degradation. Bindingof Wnts to their receptors results in disruption of the β-catenincomplex and inhibition of β-catenin degradation. This results in theaccumulation of β-catenin in the cytoplasm and nucleus where itinteracts with TCF/LEF proteins to regulate gene expression. Mutationsin APC, β-catenin, or axin have been reported to increase the nuclearaccumulation of β-catenin in cancers of epithelial origin.

The accumulation of β-catenin in the cytoplasm and nucleus has beenreported in tumors with or without β-catenin mutations. In colorectalcancers, APC is mutated in 80% of all cases. In cases without APCmutations, β-catenin mutations are found in 50% of the cases.Accumulation of β-catenin is reported to occur in a very high percentageof cases in hepatoblastomas even though β-catenin is mutated in only 34%of the samples (Blaker et al., 1999 Genes Chromosomes Cancer25:399-402). In hepatocellular carcinomas, β-catenin accumulationresults from β-catenin mutations or axin mutation, but rarely APCmutations. Forty-two percent of samples in anaplastic thyroiddemonstrate nuclear accumulation of β-catenin. Further, this highaccumulation has been reported to correlate with a decrease in survivalrate (Garcia-Rostan et al. 1999 Cancer Res. 59:1811-5). Rubinfeld et al.reported abnormal β-catenin regulation in 30% of melanoma cell lines(1997 Science 275:1790-2). Uterine endometriuim is reported to beassociated with β-catenin accumulation in both samples that containβ-catenin mutations and samples without β-catenin mutations (Fukuchi etal. 1998 Cancer Res. 58:3526-3528.) Iwao et al. report that 63% of boneand soft-tissue tumors lacking a specific β-catenin mutation stilldemonstrate β-catenin accumulation (1999 Jpn. J. Cancer Res.90:205-209).

Lin et al. reported that immunohistochemical analysis of cyclin D1 andβ-catenin in breast tumors indicated that of 53 samples positive forcyclin D1, 49 of those were also β-catenin positive with β-cateninobserved in both the nucleus and cytoplasm (2000 Proc. Natl. Acad. Sci.USA 97:4262-4266). A relationship between β-catenin and cyclin D1 hasbeen reported for colon cancer and hepatocellular carcinoma (Tetsue etal. 1999 Nature 398:422-426; Ueta et al. 2002 Oncology Reports9:1197-1203). Cyclin D1 is reported to be involved in the pathogenesisof squamous cell carcinoma (Xu et al. 1994 Int J. Cancer 59:383-387).

NSAIDs have been reported to affect β-catenin activity. For example,both aspirin and indomethacin have been reported to inhibittranscription of the β-catenin/TCF target cyclin D1 (Dihlmann et al.2001 Oncogene 20:645-53). Sulindac was reported to decrease β-catenin inintestinal tumors from Min/+ mice (McEntee et al. 1999 Carcinogenesis20:635-640). Noda et al., report that etodolac increases the expressionand cytoplasmic accumulation of cytoplasmic E-cadherin in Caco2 cells,but had no quantitative change in β-catenin expression (2002 J.Gastorenterol. 37(11):896-904).

Peroxisome proliferators-activated receptors (PPARs) are nuclear hormonereceptors that have been reported to be involved in many cellularprocesses, including lipid metabolism and disease-related processes.PPARs form dimers with retinoid-X receptor and mediate their effectsafter ligand binding through gene transcription.

Three isoforms of PPAR are known to date-α, γ, and δ. PPARα is highlyexpressed in liver and has been reported to stimulate lipid metabolism.PPARγ is highly expressed in adipose tissue and is reported to beinvolved in activating adipogeneisis. PPARγ is reported to be involvedin insulin resistance and a number of neoplastic processes includingcolorectal cancer. Shimada et al. hypothesize that activation of PPARγsignaling may compensate for deregulated c-myc expression in cells withmutated APC (2002 Gut 50:658-664). Ohta et al. report that a PPARγligand can cause a shift in β-catenin from the nucleus to the cytoplasmand induction of differentiation in pancreatic cancer cells (2002 Int J.Oncol. 21:37-42). PPARδ is expressed in many tissues and organs with thehighest expression are brain, colon, and skin. Investigators haveimplicated PPARδ in cholesterol efflux, colon cancer, embryoimplantation, preadipocyte proliferation and epidermal maturation.Investigators report that PPARδ is a downstream target ofβ-catenin/TCF-4 transcription complex (He et al., 1999 Cell 99:335-345).Also, PPARδ mRNA is reported to be overexpressed in many colorectalcancers.

NSAIDs have been reported to activate PPAR receptors (Lehmann et al.1997 J. Biol. Chem. 272:3406-3410). Researchers also report that NSAIDsmay inhibit PPARδ, which might contribute to the chemoprotective effectsof NSAIDs in preventing colorectal cancers (He et al. 1999).

Epidemiological studies indicate that NSAIDs may reduce or prevent theoccurrence of Alzheimer's disease. A connection between the COX pathwayand Alzheimer's disease has been reported and is mainly based onepidemiological studies. Studies indicate that Cox-2 is up-regulated inareas of the brain related to memory (Hinz et al. 2002 J. Pharm. Exp.Ther. 300:367-375). Weggen et al. report that some NSAIDs may reduce thepathogenic amyloid β peptide, Aβ42, by as much as 80% (2001 Nature414:212-216). This reduction has been reported to occur in aCOX-independent mechanism (Eriksen et al. 2002 J. Clinical Invest.112:440-449). Eriksen also report that flurbiprofen and its enantiomerslower Aβ42 by targeting the γ-secretase complex that produces Aβ fromamyloid β protein precursor. U.S. Pat. No. 6,255,347 discloses the useof R-ibuprofen for the treatment or prevention of Alzheimer's disease.

Analogs of etodolac are known in the art see, for example, U.S. Pat.Nos. 5,830,911; 5,824,699; 5,776,967; 5,420,289; 4,748,252; 4,686,213;4,070,371; 3,939,178; and 3,843,681.

The use of etodolac and enantiomers of etodolac to treat cancer isdescribed in U.S. Pat. Nos. 6,573,292; 6,545,034; and 5,955,504.

The use of NSAIDs to treat inflammation, cancer, and angiogenesis havebeen reported in the art see, for example, U.S. Pat. Nos. 5,972,986;6,025,353; 5,955,504; and 5,561,151.

SUMMARY OF THE INVENTION

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein:

wherein:

(a) X is C, S or O;

(b) R₁ is hydrogen; halogen; —CN; —NO₂; —OH; —SH; or an unsubstituted orsubstituted moiety selected from alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substitutedgroups are substituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, —CN,—NO₂, —OH, —SH, unsubstituted alkyl, unsubstituted alkenyl,unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstitutedalkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted heteroaryl, and —(CH₂)_(z)CN where z isan integer from 0 to 6;

(c) R₂, R₃, R₄ and R₅ are each independently hydrogen; halogen; —CN;—NO₂; —OH; —SH; or an unsubstituted or substituted moiety selected fromlower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, andheteroaryl;

(d) R₆, R₇, R₈ and R₉ are each independently hydrogen; halogen; —CN;—NO₂; —OH; —SH; or an unsubstituted or substituted moiety selected fromalkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, wherein at least one of R₆, R₇, R₈ and R₉ is anunsubstituted or substituted moiety selected from aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl;

(e) R₁₀ is hydrogen; or an unsubstituted or substituted moiety selectedfrom lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl,heterocycloalkyl, and cycloalkyl;

(f) Y is an unsubstituted or substituted moiety selected from alkyl,alkenyl, and alkynyl; and

(g) Z is a moiety selected from —OH, —NH₂, —SH, —S(O)₂NH₂, —SO₂OH,—S(O)H, —NHC(O)H, C(O)NH₂, unsubstituted or substituted with one or twosuitable substituents selected from the group consisting of alkyl,haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl each independently substituted with one, two or threesuitable substituents;

wherein R₁ and Y may cyclize to form an unsubstituted or substitutedcycloalkyl group or an unsubstituted or substituted heterocycloalkylgroup;

or a pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or

pharmaceutically acceptable salt thereof.

In some embodiments, the substituted groups in R₂, R₃, R₄, R₅, R₆, R₇,R₈, R₉ and R₁₀ of Formula I are substituted with one, two or threesuitable substituents each independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —NHOH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH₂, —NHC(NH)NH₂,—C(S)NH₂, —NHC(S)NH₂, —NHC(O)NH₂, —S(O₂)H, —S(O)H, —NH₂, —C(O)NH₂,—OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O₂)H, —OS(O)H, —OSH,—SC(O)H, —S(O)C(O)OH, —SO₂C(O)OH, —NHSH, —NHS(O)H, —NHSO₂H, —C(O)SH,—C(O)S(O)H, —C(O)S(O₂)H, —C(S)H, —C(S)OH, —C(SO)OH, —C(SO₂)OH, —NHC(S)H,—OC(S)H, —OC(S)OH, —OC(SO₂)H, —S(O₂)NH₂, —S(O)NH₂, —SNH₂, —NHCS(O₂)H,—NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or substituted withone, two or three suitable substituents each independently selected fromthe group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where zis an integer from 0 to 6, —OR_(c), —NR_(c)OR_(c), —NR_(c)R_(c),—C(O)NR_(c), —C(O)OR_(c), —C(O)R_(c), —NR_(c)C(O)NR_(c)R_(c),—NR_(c)C(O)R_(c), —OC(O)OR_(c), —OC(O)NR_(c)R_(c), —SR_(c),unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls, where R_(c) ishydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstitutedalkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, or unsubstituted heteroaryl, or two or more R_(c)groups together cyclize to form part of a heteroaryl or heterocycloalkylgroup unsubstituted or substituted with an unsubstituted alkyl group.

In other embodiments, the substituted groups in R₂, R₃, R₄, R₅, R₆, R₇,R₈, R₉, and R₁₀ of Formula I are substituted with one, two or threesuitable substituents each independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein X is S or O; R₁ ishydrogen; or an unsubstituted moiety selected from lower alkyl, loweralkenyl, lower alkynyl, aryl, heteroaryl, heterocycloalkyl, andcycloalkyl; R₂, R₃, R₄, and R₅ are each independently hydrogen; or anunsubstituted moiety selected from lower alkyl, lower alkynyl, loweralkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; R₆, R₇, R₈, and R₉ areeach independently hydrogen; or an unsubstituted or substituted moietyselected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one, butnot more than two, of R₆, R₇, R₈, and R₉ is an unsubstituted orsubstituted moiety selected from aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkenyl, and alkynyl; and R₁₀ is hydrogen; or anunsubstituted moiety selected from lower alkyl, lower alkenyl, loweralkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein, wherein X is O; R₁ is anunsubstituted alkyl group or unsubstituted aryl group; R₂, R₃, R₄, andR₅ are each hydrogen; R₇ is an unsubstituted or substituted moietyselected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and R₁₀is hydrogen. In some embodiments, R₉ is an unsubstituted alkyl group. Inother embodiments, Y is an unsubstituted alkyl group. In still otherembodiments Z is hydroxyl. In still other embodiments, R₇ is an aryl orheteroaryl group unsubstituted or substituted with one, two or threesuitable substituents each independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein where X is O; R₁ is anunsubstituted lower alkyl group or unsubstituted aryl group; R₂, R₃, R₄,and R₅ are each hydrogen; R₉ is an unsubstituted or substituted moietyselected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; and R₁₀ is hydrogen. In some embodiments, R₇ is anunsubstituted lower alkyl group. In other embodiments, Y is anunsubstituted lower alkyl group. In further embodiments, Z is hydroxyl.In still other embodiments, R₇ is an aryl or heteroaryl groupunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting of:halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH,—OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CNwhere z is an integer from 0 to 6, unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein where X is O; R₁ is anunsubstituted moiety selected from aryl, alkyl, and lower-alkoxy; R₂,R₃, R₄, and R₅ are each hydrogen; R₆ and R₈ are each hydrogen orhalogen; R₇ is an unsubstituted or substituted moiety selected from aryland heteroaryl; R₉ is selected from halogen; unsubstituted alkyl; and anunsubstituted or substituted moiety selected from aryl, heteroaryl,cycloalkyl, alkenyl, and alkynyl; and R₁₀ is hydrogen; wherein thesubstituted groups in R₇ and R₉ are substituted with one, two or threesuitable substituents independently selected from the group consistingof: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH,—OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CNwhere z is an integer from 0 to 6, unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In someembodiments, Y is an unsubstituted lower alkyl group. In otherembodiments, Z is hydroxyl.

Also provided herein are compounds of Formula I, pharmaceuticalcompositions comprising them, and methods of using them:

wherein:

(a) X is C, S or O;

(b) R₁ is hydrogen; halogen; —CN; —NO₂; —OH; —SH; or an unsubstituted orsubstituted moiety selected from alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substitutedgroups are substituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, —CN,—NO₂, unsubstituted alkyl, unsubstituted alkenyl, unsubstitutedheteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl,unsubstituted aryl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted heteroaryl, and —(CH₂)_(z)CN where z isan integer from 0 to 6;

(c) R₂, R₃, R₄ and R₅ are each independently hydrogen; halogen; —CN;—NO₂; —OH; —SH; or an unsubstituted or substituted moiety selected fromlower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, andheteroaryl;

(d) R₆, R₇, R₈ and R₉ are each independently hydrogen; halogen; —CN;—NO₂; —OH; —SH; or an unsubstituted or substituted moiety selected fromalkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl, wherein at least one of R₆, R₇, R₈ and R₉ is anunsubstituted or substituted moiety selected from aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl;

(e) R₁₀ is hydrogen; or an unsubstituted or substituted moiety selectedfrom lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl,heterocycloalkyl, and cycloalkyl;

(f) Y is an unsubstituted or substituted moiety selected from alkyl,alkenyl, and alkynyl; wherein the substituted moiety is substituted withone, two or three substitutents each independently selected fromhalogen; —CN; —NO₂; —OH; —SH; unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and

(g) Z is a moiety selected from —OH, —SH, —SO₂, —SO₂NH₂, —SO₂OH, —S(O)H,—NH₂, —NHC(O)H, C(O)NH₂, unsubstituted or substituted with one or twosuitable substituents selected from the group consisting of alkyl,haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl;

wherein R₁ and Y may cyclize to form an unsubstituted or substitutedcycloalkyl group or an unsubstituted or substituted heterocycloalkylgroup; or a pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt thereof.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein the substituted groupsin R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are substituted with one, twoor three suitable substituents independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —NHOH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH₂, —NHC(NH)NH₂,—C(S)NH₂, —NHC(S)NH₂, —NHC(O)NH₂, —S(O₂)H, —S(O)H, —NH₂, —C(O)NH₂,—OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O₂)H, —OS(O)H, —OSH,—SC(O)H, —S(O)C(O)OH, —SO₂C(O)OH, —NHSH, —NHS(O)H, —NHSO₂H, —C(O)SH,—C(O)S(O)H, —C(O)S(O₂)H, —C(S)H, —C(S)OH, —C(SO)OH, —C(SO₂)OH, —NHC(S)H,—OC(S)H, —OC(S)OH, —OC(SO₂)H, —S(O₂)NH₂, —S(O)NH₂, —SNH₂, —NHCS(O₂)H,—NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or substituted withone, two or three suitable substituents each independently selected fromthe group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where zis an integer from 0 to 6, —OR_(c), —NR_(c)OR_(c), —NR_(c)R_(c),—C(O)NR_(c), —C(O)OR_(c), —C(O)R_(c), —NR_(c)C(O)NR_(c)R_(c),—NR_(c)C(O)R_(c), —OC(O)OR_(c), —OC(O)NR_(c)R_(c), —SR_(c),unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls, where R_(c) ishydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstitutedalkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, or unsubstituted heteroaryl, or two or more R_(c)groups together cyclize to form part of a heteroaryl or heterocycloalkylgroup unsubstituted or substituted with an unsubstituted alkyl group.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein R₁ is hydrogen; or anunsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy,lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, loweralkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl. Insome embodiments, wherein R₁ cyclizes with Y to from a substituted orunsubstituted cycloalkyl or heterocycloalkyl group.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₂, R₃, R₄ and R₅ areeach independently hydrogen; or an unsubstituted moiety selected fromlower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, andheteroaryl. In some embodiments, R₂, R₃, R₄ and R₅ are eachindependently hydrogen.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₆, R₇, R₈ and R₉ areeach independently hydrogen; or an unsubstituted or substituted moietyselected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one, butnot more than two, of R₆, R₇, R₈ and R₉ is an unsubstituted orsubstituted moiety selected from aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkenyl, and alkynyl. In some embodiments, thesubstituted moieties are each independently selected from the groupconsisting of halogen, —CN, alkyl, alkoxy, —NH₂, —O-haloalkyl, —CH(O),haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, —OH,—C(O)₂-alkyl, and —C(O)₂H.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₆ is hydrogen orhalogen.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₇ is hydrogen;halogen; or an unsubstituted or substituted moiety selected from aryl,heteroaryl, alkyl, heterocycloalkyl, and alkoxy, wherein the substitutedmoiety is substituted with one, two or three substituents independentlyselected from the group consisting of —OH, —C(O)₂-alkyl, —C(O)₂H,alkoxy, —O-haloalkyl, halogen, alkyl, haloalkyl, and —NH₂.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₈ is hydrogen orhalogen.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₉ is hydrogen;halogen; or an unsubstituted or substituted moiety selected from alkyl,aryl, heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl,haloalkyl, wherein the substituted moiety is substituted with one, twoor three substitutents independently selected from the group consistingof alkyl, —C(O)H, —CN, halogen, alkoxy, aryl, and —C(O)₂H.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein R₁₀ is hydrogen,alkyl, or alkyl-aryl. In some embodiments, X is O. In other embodiments,Y is lower alkyl.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein Z is hydroxy. In someembodiments, Z is —(C)(O)NH₂ unsubstituted or substituted with one ortwo alkyl groups. In other embodiments, Z is hydroxyl, unsubstituted orsubstituted lower alkoxy, amino, lower alkylamino, di(lower)alkylamino,arylamino, (aryl)lower alkylamino, di(aryl)lower alkylamino,di(aryl)amino, (heterocycle)amino, (heterocycle)lower alkylamino,di(heterocycle)lower alkylamino, and di(heterocycles)amino. Compounds ofFormula I, pharmaceutical compositions comprising them, and methods ofusing them are provided herein wherein:

(a) X is S or O;

(b) R₁ is hydrogen; or an unsubstituted moiety selected from loweralkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, loweralkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, andcycloalkyl;

(c) R₂, R₃, R₄ and R₅ are each independently hydrogen; or anunsubstituted moiety selected from lower alkyl, lower alkynyl, loweralkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;

(d) R₆, R₇, R₈ and R₉ are each independently hydrogen; or anunsubstituted or substituted moiety selected from alkyl, alkenyl,alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, wherein the substituted moieties are eachindependently selected from the group consisting of halogen, —CN, alkyl,alkoxy, —NH₂, —O-haloalkyl, —CH(O), haloalkyl, aryl, heteroaryl,heterocycloalkyl, alkenyl, alkynyl, —OH, —C(O)₂-alkyl, and —C(O)₂H; and

(e) R₁₀ is hydrogen; or an unsubstituted moiety selected from loweralkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl,heterocycloalkyl, and cycloalkyl.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein:

(a) X is O;

(b) R₁ is an unsubstituted alkyl group or unsubstituted aryl group;

(c) R₂, R₃, R₄ and R₅ are each hydrogen;

(d) R₇ is an unsubstituted or substituted moiety selected from aryl,heteroaryl, cycloalkyl and heterocycloalkyl;

(e) R₉ is an unsubstituted alkyl group;

(f) ₁₀ is hydrogen.

(g) an unsubstituted alkyl group; and

(h) Z is hydroxyl.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein at least one of R₆,R₇, R₈ and R₉ is an aryl group unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl,heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, —(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH,—C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls. In some embodiment, atleast one of R₆, R₇, R₈ and R₉ is a heteroaryl group unsubstituted orsubstituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls. In other embodiment,at least one of R₆, R₇, R₈ and R₉ is a heterocycloalkyl groupunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting of:halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH,—OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CNwhere z is an integer from 0 to 6, unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein:

(a) X is O or S;

(b) R₁ is an unsubstituted lower alkyl group or unsubstituted arylgroup;

(c) R₂, R₃, R₄ and R₅ are each hydrogen;

(d) R₆ is hydrogen or halogen;

(e) R₇ is an unsubstituted or substituted moiety selected from alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

(f) R₈ is hydrogen or halogen;

(g) R₉ is an unsubstituted or substituted moiety selected from alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and

(h) R₁₀ is hydrogen. In some embodiment, Y is an unsubstituted loweralkyl group and Z is hydroxyl.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein at least one of R₇ orR₉ is an aryl group unsubstituted or substituted with one, two or threesuitable substituents each independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls. In some embodiment, atleast one of R₇ or R₉ is an heteroaryl group unsubstituted orsubstituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls. In other embodiments,at least one of R₇ or R₉ is an alkenyl group unsubstituted orsubstituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls. In still otherembodiments, at least one of R₇ or R₉ is an alkynyl group unsubstitutedor substituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.

Compounds of Formula I, pharmaceutical compositions comprising them, andmethods of using them are provided herein wherein

(a) X is O;

(b) R₁ is an unsubstituted moiety selected from aryl, alkyl, andlower-alkoxy;

(c) R₂, R₃, R₄, and R₅ are each hydrogen;

(d) R₆ and R₈ are each hydrogen or halogen; R₇ is an unsubstituted orsubstituted aryl or heteroaryl group; R₉ is selected from halogen;unsubstituted alkyl; and an unsubstituted or substituted moiety selectedfrom aryl, heteroaryl, cycloalkyl, alkenyl, and alkynyl;

(e) R₁₀ is hydrogen;

(f) Y is an unsubstituted lower alkyl group; and

(g) Z is hydroxyl;

wherein the substituted groups in R₇ and R₉ are substituted with one,two or three suitable substituents independently selected from the groupconsisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,—(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH, —C(O)H,—OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.

In some embodiments, R₉ is a branched alkyl group. In other embodiments,R₇ is not hydrogen. In still other embodiments, Y-Z is an unsubstitutedethoxy group. In yet other embodiments, R₁ is an unsubstituted ethylgroup. In yet other embodiments, Z is a moiety selected from —OH, —SHand —OC(O)NH₂.

Pharmaceutical compositions comprising a therapeutically effectiveamount of a compound of Formula I and a pharmaceutically acceptablecarrier are provided herein.

Exemplary compounds within Formulas I are shown below: NO. STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

or pharmaceutically acceptable salts thereof.

Pharmaceutical compositions comprising a therapeutically effectiveamount of a prodrug, active metabolite, or pharmaceutically acceptablesalt of a compound of Formula I, as well as pharmaceutically acceptablesalts of such active metabolites, are also provided herein.

Methods of treating a neoplasia comprising administering to a subject inneed thereof a therapeutically effective amount of a compositioncomprising a compound of Formula I are provided herein. In someembodiments, the neoplasia is a hematological cancer. In otherembodiments, the neoplasia is selected from leukemias such as chroniclymphocytic leukemia, myelomas such as multiple myeloma, and lymphomas.In still other embodiments, the cancer is selected from brain cancer,bone cancer, basal cell carcinoma, adenocarcinoma, gastrointestinalcancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer,stomach cancer, colon cancer, liver cancer, bladder cancer, pancreascancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skincancer, prostate cancer, and renal cell carcinoma.

Methods for treating cancer by administering a composition comprising atherapeutically effective amount of a composition of Formula I given incombination with another antineoplastic agent are provided herein. Insome embodiments, the antineoplastic agent is an alkylating agent. Inother embodiments, the alkylating agent is selected from the groupconsisting of bendamustine, chlorambucil, cyclophosphamide andmelphalan. In still other embodiments, the antineoplastic agent is aglucocorticoid. In yet other embodiments, the glucocorticoid isprednisone. In some embodiments, the glucocorticoid is given incombination with additional antineoplastic agents.

Methods for treating a disease mediated by β-catenin in a subject inneed of such therapy wherein a therapeutically effective amount of acompound of Formula I is administered to the subject, are providedherein.

Methods for treating a disease mediated by Cyclin D1 in a subject inneed of such therapy wherein a therapeutically effective amount of acompound of Formula I is administered to the subject, are also providedherein.

Methods for reducing or preventing the development of Alzheimer'sdisease comprising administering to a subject in thereof atherapeutically effective amount of a composition comprising a compoundof Formula I are provided herein. In some embodiments, the methodcomprises administering to a mammal in need of such treatment atherapeutically effective amount of: (a) at least one compound,pharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite of Formula I; and (b) at least oneagent selected from the group consisting of estrogen, risperidone, athiobenzodiazepine, ampakine,[N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, acholinesterase inhibitor, donepezil hydrochloride, rivastigminetartrate, galantamine, NGF, and metrifonate.

Methods for treating a disease in a mammal treatable by administrationof a COX-1 and/or COX-2 inhibitor comprising administering to the mammala therapeutically effective amount of a compound of Formula I whichinhibits one or both of COX-1 or COX-2 are provided herein. In someembodiments, the disease is an inflammatory disease.

Methods for treating a hyperplastic disease in a mammal comprisingadministration to the mammal a therapeutically effective amount of acompound of Formula I are provided herein.

Methods for inhibiting or delaying the onset of a neoplasia in a mammalin need of such treatment comprising administration to the mammal atherapeutically effective amount of a compound of Formula I are providedherein. In some embodiments, the neoplasia is selected from the groupconsisting of adenomatous polyps, gastrointestinal cancer, liver cancer,bladder cancer, cervical cancer, prostate cancer, lung cancer, breastcancer, and skin cancer.

Methods for treating, inhibiting or delaying the onset of uncontrolledor abnormal angiogenesis in a subject in need of such treatment,inhibition or delay, wherein the uncontrolled or abnormal angiogenesisis selected from the group consisting of metastasis, corneal graftrejection, ocular neovascularization, retinal neovascularization,diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma,gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx,avascular necrosis of bone, and endometriosis, and the method comprisestreating the subject with a therapeutically effective amount of acompound of Formula I are provided herein.

Pharmaceutical compositions for the treatment of one or more conditionsselected from the group consisting of arthritis, fever, common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer, tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis, aorticaneurysm, periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neuro-degenerative disorders, autoimmune disorders,Huntington's disease, Parkinson's disease, migraine, depression,peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders, myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases, sepsis, premature labor, hypoprothrombinemia, hemophilia,thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity,schizophrenia, kidney disease, Rickettsial infections, Protozoandiseases, reproductive disorders, obesity, and septic shock in a mammal,comprising an effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof effective in such treatmentsand a pharmaceutically acceptable carrier are provided herein.

Methods of treating a neoplasia in a subject in need of treatment wherethe subject is treated with a composition comprising a compound ofFormula I. Neoplasms that can be treated include, but are not limitedto, hematological cancers, such as leukemias, myelomas and lymphomas,brain cancer, bone cancer, epithelial cell derived neoplasia (epithelialcarcinoma) such as basal cell carcinoma, adenocarcinoma,gastrointestinal cancer such as lip cancer, mouth cancer, esophagealcancer, small bowel cancer, stomach cancer, colon cancer, liver cancer,bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lungcancer, breast cancer, skin cancer such as squamous cell and basal cellcancers, prostate cancer, renal cell carcinoma, and other known cancersthat effect epithelial cells throughout the body and cancers of the bonemarrow.

Methods for treating one or more conditions selected from the groupconsisting of arthritis, fever, common cold, dysmenorrhea, menstrualcramps, inflammatory bowel disease, Crohn's disease, emphysema, acuterespiratory distress syndrome, obesity, asthma, bronchitis, chronicobstructive pulmonary disease, Alzheimer's disease, organ transplanttoxicity, cachexia, allergic reactions, allergic contacthypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa,congestive heart failure, myocardial infarction, stroke, cerebralischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerativedisorders, autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain, gingivitis,cerebral amyloid angiopathy, nootropic or cognition enhancement,amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis,corneal injury, macular degeneration, conjunctivitis, abnormal woundhealing, muscle or joint sprains or strains, tendonitis, skin disorders,myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes,tumor invasion, tumor growth, tumor metastasis, corneal scarring,scleritis, immunodeficiency diseases, sepsis, premature labor,hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet'ssyndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsialinfections, Protozoan diseases, reproductive disorders, and septic shockin a mammal, comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof effective in treating such a condition, areprovided herein.

In some embodiments, methods for treating a hyperplastic disease in amammal by administering to the mammal a therapeutically effective amountof a compound of Formula I.

In other embodiments, methods for treating, inhibiting, or delaying theonset of uncontrolled or abnormal angiogenesis in a subject in need ofsuch treatment, inhibition, or delay by administering a therapeuticallyeffective amount of a compound of Formula I, are provided. In oneembodiment of this method, the uncontrolled or abnormal angiogenesis tobe treated is selected from the group including, but not limited to,metastasis, corneal graft rejection, ocular neovascularization, retinalneovascularization, diabetic retinopathy, retrolental fibroplasia,neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibromaof the nasopharynx, avascular necrosis of bone, and endometriosis.

In still other embodiments, methods for selecting a subject fortreatment of a disease or condition mediated by β-catenin where themethod involves obtaining a sample of the subject's tumor, determiningif β-catenin is activated in the tumor, and treating the subject with anagent that modulates β-catenin activity. In one related method,β-catenin activation is determined with immunohistochemical methods.

In still other embodiments, methods for selecting a subject fortreatment of a disease or condition mediated by Cyclin D1 where themethod involves obtaining a sample of the subject's tumor, determiningif Cyclin D1 is overexpressed in the tumor, and treating the subjectwith an agent that modulates Cyclin D1 activity. Preferred compounds foruse in the method are compounds of Formula I. In one related method,Cyclin D1 overexpression is determined using quantitative PCR.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows inhibition of β-catenin:TOP flash by R-etodolac andcompounds of the invention.

FIG. 2 shows inhibition of Cyclin D1 mRNA expression by R-etodolac andcompounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

To more readily facilitate an understanding of the invention and itspreferred embodiments, the meanings of terms used herein will becomeapparent from the context of this specification in view of common usageof various terms and the explicit definitions of other terms provided inthe glossary below or in the ensuing description.

Glossary of Terms

As used herein, the terms “comprising,” “including,” and “such as” areused in their open, non-limiting sense.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise.

In accordance with a convention used in the art,

is used in structural formulae herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

In accordance with a convention used in the art, the symbol

represents a methyl group,

represents an ethyl group,

represents a cyclopentyl group, etc.

The term “alkyl” as used herein refers to a straight- or branched-chainalkyl group having one to twelve carbon atoms. Exemplary alkyl groupsinclude methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and the like. The term “lower alkyl” designates an alkylhaving from 1 to 6 carbon atoms (a C₁₋₆-alkyl).

The term “heteroalkyl” as used herein refers to straight- andbranched-chain alkyl groups having from one to twelve atoms containingone or more heteroatoms selected from S, O, and N. The term “lowerheteroalkyl” designates a heteroalkyl having from 1 to 6 carbon atoms (aC₁₋₆-heteroalkyl).

The term “alkenyl” means an alkyl radical having one or more doublebonds and two to twelve carbon atoms. Alkenyl groups containing three ormore carbon atoms may be straight or branched. Alkenyl groups as usedherein include either the cis or trans configurations. Illustrativealkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and the like. The term “lower alkenyl”designates an alkyl having from 1 to 6 carbon atoms (a C₁₋₆-alkenyl).

The term “allyloxy” refers to an alkenyloxy group which is CH₂═CHCH₂—O—.

The term “alkynyl” means an alkyl radical having one or more triplebonds and two to twelve carbon atoms. Alkynyl groups containing three ormore carbon atoms may be straight or branched. Alkynyl groups as usedherein include either the cis or trans configurations. Illustrativealkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl,2-methylbut-2-ynyl, hex-2-ynyl, and the like. The term “lower alkynyl”designates an alkyl having from 1 to 6 carbon atoms (a C₁₋₆-alkynyl).

The term “aryl” (Ar) refers to a monocyclic, or fused or spiropolycyclic, aromatic carbocycle (ring structure having ring atoms thatare all carbon) having from three to twelve ring atoms per ring.Illustrative examples of aryl groups include the following moieties:

The term “heteroaryl” (heteroAr) refers to a monocyclic, or fused orspiro polycyclic, aromatic heterocycle (ring structure having ring atomsselected from carbon atoms as well as nitrogen, oxygen, and sulfurheteroatoms) having from three to twelve ring atoms per ring.Illustrative examples of heteroaryl groups include the followingmoieties:

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic or fused or spiro polycyclic, carbocycle having from three totwelve ring atoms per ring. Illustrative examples of cycloalkyl groupsinclude the following moieties:

A “heterocycloalkyl” refers to a monocyclic, or fused or spiropolycyclic, ring structure that is saturated or partially saturated andhas from three to twelve ring atoms per ring selected from C atoms andN, O, and S heteroatoms. Illustrative examples of heterocycloalkylgroups include:

The term “alkoxy” refers to —O-alkyl. Illustrative examples includemethoxy, ethoxy, propoxy, and the like.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

Unless otherwise defined, the term “substituted” as used herein means atleast one hydrogen atom is replaced with a substituent.

The term “unsubstituted” means that the specified group bears nosubstituents.

The term “lower” when referring to a group such as an alkyl, alkenyl,alkynyl, alkoxy or other group refers to such a group having up to 6carbon atoms.

As used herein “tumors” or “neoplasms” include growths of tissue cellswherein multiplication of cells is uncontrolled and progressive. Somesuch growths are benign, but others are termed malignant and can lead todeath of the organism. Malignant neoplasms, or cancers are distinguishedfrom benign growths in that in addition to exhibiting aggressivecellular proliferation can invade surrounding tissues and metastasize.Malignant neoplasms may be characterized by showing a greater loss ofdifferentiation and organization relative to one another and surroundingtissues.

“Hyperplasia” refers to the abnormal multiplication or increase in thenumber of normal cells in normal arrangement in a tissue.

The term “subject” for purposes of treatment includes any human oranimal subject who has any one of the known diseases or conditionsdescribed herein, e.g., cancer, hyperplasia, inflammation, Alzheimer's,and abnormal angiogenesis. For methods of prevention, the subject is anyhuman or animal subject, and preferably is a human subject who is atrisk for the disease or conditions described herein, e.g., cancer. Thesubject may be at risk due to a genetic predisposition, and/or exposureto various agents, including chemicals and viral agents. Besides beinguseful for human treatment, the compounds described herein are alsouseful for veterinary treatment of mammals, including companion animalsand farm animals, such as horses, dogs, cats, cows, sheep and pigs.Preferably, subject means a human.

As used herein “a disease mediated by β-catenin” means a disease that isassociated with changes in β-catenin regulation such that the itslevels, distribution and/or association with other proteins in thecytoplasm and nucleus differ from that found in normal cells. Changes inβ-catenin levels, associations, and/or distribution, e.g., nuclearaccumulation may result from mutations in β-catenin, APC, axin or otherproteins involved in the trafficking of β-catenin. β-cateninaccumulation, levels and/or distribution may also be affected by changesin the wnt/fzd signaling pathway. β-catenin accumulation in the nucleusmay lead to the transcription of genes involved in tumorgenesis, such ascyclin D1 and c-myc.

As used herein “activated β-catenin” represents β-catenin that is notmarked for degradation.

As used herein “a disease mediated by Cyclin D1” means a disease that isassociated with changes in Cyclin D1 expression such that the itslevels, distribution and/or association with other proteins in the celldiffer from that found in normal cells.

As used herein “angiogenesis” is the development of new blood vesselsinto a tissue or organ. Under normal conditions, angiogenesis isobserved in wound healing and embryonal development. Uncontrolled orabnormal angiogenesis is associated with neoplastic disease, tumormetastasis and other angiogenesis-related diseases.

“A pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of thespecified compound and that is not biologically or otherwiseundesirable.

As used herein a “pharmaceutically acceptable prodrug” is a compoundthat may be converted under physiological conditions or by solvolysis tothe specified compound or to a pharmaceutically acceptable salt of suchcompound.

The term “a pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound or salt thereof.

An “effective amount” is intended to mean that amount of an agent that,when administered to a subject in need of such treatment, is sufficientto effect treatment for a disease and/or condition associated withβ-catenin, COX, PPAR, Cyclin D and/or Aβ42. Thus, e.g., atherapeutically effective amount of a compound of the Formula I, salt,active metabolite or prodrug thereof is a quantity sufficient tomodulate, regulate, or inhibit the activity of β-catenin, COX, PPAR,Cyclin D and/or Aβ42 such that a disease and/or condition which ismediated by that activity is reduced or alleviated.

The terms “treating”, “treat” and “treatment” refer to any treatment ofa COX, β-catenin, PPAR, or amyloid-β mediated disease and/or conditionin a mammal, particularly a human, and include: (i) preventing thedisease or condition from occurring in a subject which may bepredisposed to the condition, for example subjects with accumulated Aβpeptides, such that the treatment constitutes prophylactic treatment forthe pathologic condition; (ii) modulating or inhibiting the disease orcondition, i.e., arresting its development; (iii) relieving the diseaseor condition, i.e., causing regression of the disease or condition; or(iv) relieving and/or alleviating disease or condition or the symptomsresulting from the disease or condition, e.g., relieving an inflammatoryresponse without addressing the underlining disease or condition.

By “efficacious levels” is meant levels in which the effects ofβ-catenin, COX, PPAR, Cyclin D and/or Aβ42 activity or amounts are, at aminimum, regulated.

The phrase “conjunctive therapy” (or “combination therapy”), in defininguse of a compound of the invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singleformulation having a fixed ratio of these active agents, or in multiple,separate formulations for each agent.

Compounds

Applicants have discovered compounds, as represented by Formulas I,which possess COX inhibitory activity, β-catenin inhibitory activity,cyclin D1 activity, and/or are cytotoxic to cancer cell lines.

Provided herein are compounds represented by Formulas I:

or a pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt thereof, wherein R₁-R₁₀,X, Y, Z and n are as defined herein.

The compounds of Formula I may exhibit the phenomenon of tautomerism.While Formulas I cannot expressly depict all possible tautomeric forms,it is to be understood that Formula I are intended to represent anytautomeric form of the depicted compound and are not to be limitedmerely to a specific compound form depicted by the formula drawings.

The compounds of Formula I may have one or more asymmetric centersdepending upon the nature of the various substituents on the molecule.As a consequence of these asymmetric centers, the compounds of FormulasI may exist as single stereoisomers (i.e., essentially free of otherstereoisomers), racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof are intended to be within the scope of the present invention.Preferably, the inventive compounds that are optically active are usedin optically pure form.

As generally understood by those skilled in the art, an optically purecompound having one chiral center (i.e., one asymmetric carbon atom) isone that consists essentially of one of the two possible enantiomers(i.e., is enantiomerically pure), and an optically pure compound havingmore than one chiral center is one that is both diastereomerically pureand enantiomerically pure. The compounds of the present invention can beused in a form that is at least 90% optically pure, that is, a form thatcontains at least 90% of a single isomer (80% enantiomeric excess(“e.e.”) or diastereomeric excess (“d.e.”)). In some cases, e.g., toreduce toxicity, the compounds can be used in a form that contains atleast 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95%e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.) of asingle isomer e.e. or d.e.

Additionally, Formula I are intended to cover solvated as well asunsolvated forms of the identified structures. For example, Formula Iinclude compounds of the indicated structure in both hydrated andnon-hydrated forms. Other examples of solvates include the structures incombination with isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, or ethanolamine.

In addition to compounds of Formula I, the invention includespharmaceutically acceptable prodrugs, pharmaceutically activemetabolites, and pharmaceutically acceptable salts of such compounds andmetabolites.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. See, e.g., Bertolini et al., J.Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86 (7),765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advancesin Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs(Elsevier Press 1985); Larsen, Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen et al., eds., Harwood AcademicPublishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000);Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605(1992); and Prox et al., Xenobiol., 3, 103-112 (1992).

A compound of the invention may possess a sufficiently acidic, asufficiently basic, or both functional groups, and accordingly reactwith any of a number of inorganic or organic bases, and inorganic andorganic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, g-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds and salts may exist in differentcrystal or polymorphic forms, all of which are intended to be within thescope of the present invention and specified formulas.

Therapeutically effective amounts of the agents of the invention may beused to treat or prevent diseases and/or conditions mediated bymodulation or regulation of β-catenin, COX, Aβ42, and PPAR.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjectin need of treatment, but can nevertheless be routinely determined byone skilled in the art.

The active agents of the invention may be formulated into pharmaceuticalcompositions as described below. Pharmaceutical compositions of thisinvention comprise an effective modulating, regulating, or inhibitingamount of a compound of Formula I and an inert, pharmaceuticallyacceptable carrier or diluent. In one embodiment of the pharmaceuticalcompositions, efficacious levels of the inventive agents are provided soas to provide therapeutic benefits involving modulation of β-catenin,COX, PPAR, and/or Aβ42. These compositions are prepared in unit-dosageform appropriate for the mode of administration, e.g., parenteral ororal administration.

An inventive agent can be administered in conventional dosage formprepared by combining a therapeutically effective amount of an agent(e.g., a compound of Formula I) as an active ingredient with appropriatepharmaceutical carriers or diluents according to conventionalprocedures. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

The pharmaceutical carrier employed may be either a solid or liquid.Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryof liquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the carrier or diluent may include time-delay or time-releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

A variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation will be in the form of syrup, emulsion, soft gelatincapsule, sterile injectable solution or suspension in an ampoule or vialor non-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of an inventive agent is dissolved in an aqueoussolution of an organic or inorganic acid, such as 0.3M solution ofsuccinic acid or citric acid. If a soluble salt form is not available,the agent may be dissolved in a suitable cosolvent or combinations ofcosolvents. Examples of suitable cosolvents include, but are not limitedto, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the totalvolume. In an exemplary embodiment, a compound of Formula I is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

It will be appreciated that the actual dosages of the agents used in thecompositions of this invention will vary according to the particularcomplex being used, the particular composition formulated, the mode ofadministration and the particular site, host and disease and/orcondition being treated. Optimal dosages for a given set of conditionscan be ascertained by those skilled in the art using conventionaldosage-determination tests in view of the experimental data for anagent. For oral administration, an exemplary daily dose generallyemployed is from about 0.001 to about 3000 mg/kg of body weight, withcourses of treatment repeated at appropriate intervals. In someembodiments, the daily dose is from about 1 to 3000 mg/kg of bodyweight.

Typical daily doses in a patient may be anywhere between about 500 mg toabout 3000 mgs, given once or twice daily, e.g., 3000 mg can be giventwice daily for a total dose of 6000 mg. In one embodiment, the dose isbetween about 1000 to about 3000 mgs. In another embodiment, the dose isbetween about 1500 to about 2800 mgs. In other embodiments, the dose isbetween about 2000 to about 3000 mgs.

Plasma concentrations in the subjects may be between about 100 μM toabout 1000 μM. In some embodiments, the plasma concentration may bebetween about 200 μM to about 800 μM. In other embodiments, theconcentration is about 300 μM to about 600 μM. In still otherembodiments the plasma concentration may be between about 400 to about800 μM. Administration of prodrugs is typically dosed at weight levels,which are chemically equivalent to the weight levels of the fully activeform.

The compositions of the invention may be manufactured using techniquesgenerally known for preparing pharmaceutical compositions, e.g., byconventional techniques such as mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations, whichcan be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen.For injection, the agents of the invention may be formulated intoaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carriersknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, dragees, capsules, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained using a solid excipient in admixture with the active ingredient(agent), optionally grinding the resulting mixture, and processing themixture of granules after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include: fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol; andcellulose preparations, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations, which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents, which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may alsobe formulated as a depot preparation. Such long-acting formulations maybe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) orion-exchange resins, or as sparingly soluble derivatives, for example,as a sparingly soluble salt.

An exemplary pharmaceutical carrier for hydrophobic compounds is acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. The cosolventsystem may be a VPD co-solvent system. VPD is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5%dextrose in water solution. This co-solvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a co-solvent system may bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of polysorbate 80; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars orpolysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are knownby those skilled in the art. Sustained-release capsules may, dependingon their chemical nature, release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Some of the compounds of the invention may be provided as salts withpharmaceutically compatible counter ions. Pharmaceutically compatiblesalts may be formed with many acids, including hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree-base forms.

The administration of the present invention may be for either preventionor treatment purposes. When used for the treatment and/or prevention ofneoplasia, or Alzheimer's, or for the treatment of diseases treatable byinhibiting COX, the methods and compositions described herein may beused alone or in conjunction with additional therapies known to thoseskilled in the art. Alternatively, the methods and compositionsdescribed herein may be used as conjunctive therapy. By way of example,the compounds described herein may be administered alone or inconjunction with other antineoplastic agents, glucocorticoids or othergrowth inhibiting agents or other drugs or nutrients.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which couldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, including glucocorticoids such as prednisone anddexamethasone, immunological agents, interferon-type agents and acategory of miscellaneous agents. Alternatively, other anti-neoplasticagents, such as metallomatrix proteases (MMP), SOD mimics or alpha_(v)beta₃ inhibitors may be used.

One family of antineoplastic agents which may be used in combinationwith the compounds of the inventions consists of antimetabolite-typeantineoplastic agents. Suitable antimetabolite antineoplastic agents maybe selected from the group consisting of alanosine, AG2037 (Pfizer),5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

A second family of antineoplastic agents which may be used incombination with the compounds of the invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bendamustine, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)₂,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,melphalan, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCINSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119,ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22,spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol.

Another family of antineoplastic agents which may be used in combinationwith the compounds of the invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from the group consisting of Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, alanosine, Erbamont ADR-456, aeroplysininderivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Sodaanisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-MyersBL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b,Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with the compounds of the invention include a miscellaneousfamily of antineoplastic agents selected from the group consisting ofalpha-carotene, alpha-difluoromethyl-arginine, acitretin, arsenictrioxide, Avastin® (bevacizumab), Biotec AD-5, Kyorin AHC-52, alstonine,amonafide, amphethinile, amsacrine, Angiostat, ankinomycin,anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-MyersBMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, WellcomeBW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF,chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-LambertCI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-LambertCI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711,Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B,cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine,datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, DaiichiSeiyaku DN-9693, elliprabin, elliptinium acetate, epothionesTsumuraEPMTC, erbitux, ergotamine, erlotnib, etoposide, etretinate,fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Glivec®(imatnib), Chugai GLA-43, Glaxo GR-63178, gefitinib, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, indanocine, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,mefloquine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, Rituxan® (and other anti CD20 antibodies, e.g.Bexxar®, Zevalin®), SmithKline SK&F-104864, statins (Lipitor® etc.),Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol,spirocyclopropane derivatives, spirogermanium, Unimed, SS PharmaceuticalSS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071,superoxide dismutase, Thalidomide, Toyama T-506, Toyama T-680, taxol,Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534, zometa.

Examples of radioprotective agents which may be used in the combinationchemotherapy of this invention are AD-5, adchnon, amifostine analogues,detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanines,TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofentransdermal, nabumetone, superoxide dismutase (Chiron) and superoxidedismutase Enzon.

Methods for preparation of the antineoplastic agents described above maybe found in the literature. Methods for preparation of doxorubicin, forexample, are described in U.S. Pat. Nos. 3,590,028 and 4,012,448.Methods for preparing metallomatrix protease inhibitors are described inEP 780386. Methods for preparing SOD mimics are described in EP 524,101.Methods for preparing .alpha_(v) .beta₃ inhibitors are described inWO97/08174.

Additionally, the compounds of Formula I may be administered eitheralone or in combination with other compounds effective for treatingAlzheimer's or dementia. For example, the compounds of the invention maybe administered in combination with other agents used to treatamyloid-Δ-mediated diseases or conditions, such as estrogen,risperidone, a thiobenzodiazepine, ampakine,[N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, acholinesterase inhibitor, donepezil hydrochloride, rivastigminetartrate, galantamine, NGF, and metrifonate.

Cox Inhibitors

The compounds of Formula I described herein or pharmaceuticallyacceptable salts may possess COX-inhibiting activity and possessanti-inflammatory, antipyretic, analgesic, antithrombotic, andanti-cancer activities. The compounds of Formula I and pharmaceuticallyacceptable salt thereof, therefore, are useful for treating and/orpreventing COX-mediated diseases, inflammatory conditions, pain, fever,rheumatic fever, collagen diseases, autoimmune diseases, variousimmunological diseases, thrombosis, cancer and neurodegenerativediseases in human beings or animals by using administered systemicallyor topically. More particularly, the compounds and pharmaceuticallyacceptable salts thereof are useful for treating and/or preventinginflammation and acute or chronic joint and muscle pain [e.g. rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis,juvenile arthritis, etc.], inflammatory skin condition [e.g. sunburn,burns, eczema, dermatitis, etc.], inflammatory eye condition [e.g.conjunctivitis, etc.], lung disorder in which inflammation is involved[e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.], conditions of the gastrointestinal tract associated withinflammation [e.g. aphthous ulcer, Crohn's disease, atopic gastritis,gastritis varialoforme, ulcerative colitis, coeliac disease, regionalileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, painand tumescence after operation or injury, pyrexia, pain and otherconditions associated with inflammation, particularly those in whichlipoxygenase and cyclooxygenase products are a factor, systemic lupuserythematosus, scleroderma, polymyositis, tendonitis, bursitis,periarteritisnodose, rheumatic fever, Sjogren's syndrome, Behcetdisease, thyroiditis, type I diabetes, nephrotic syndrome, aplasticanemia, myasthenia gravis, uveitis contact dermatitis, psoriasis,Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease,Parkinson's disease, symptoms associated with influenza and other viralinfections, common cold, low back and neck pain, dysmenorrheal,headache, toothache, sprains and strains, myositis, neuralgia,synovitis, arthritis including rheumatoid arthritis, degenerative jointdisease or osteoarthritis, gout, ankylosing spondylitis, bursitis,injuries following surgical and dental procedures, bone loss, or thelike. Additionally, the compounds disclosed herein or a salt thereof isexpected to be useful as therapeutical and/or preventive agents forcardiovascular or cerebrovascular diseases, the diseases caused byhyperglycemia and hyperlipemia.

The anti-inflammatory activity of the compounds of this invention may beassayed by measuring the ability of the compound to inhibit COX-1 andCOX-2. Techniques for measuring COX inhibition is described herein andin the literature, for example, see US Patent Application No.2002/0107280; Winter et al. 1962 Proc. Soc. Exp. Biol. Med. 111:544 bothincorporated herein by reference.

In still other embodiments preferred compounds of Formula I are thosecompound with no or little COX activity.

Cancer

Neoplasms treatable by the present invention include solid tumors, i.e.,carcinomas and sarcomas. Carcinomas include malignant neoplasms derivedfrom epithelial cells which infiltrate surrounding tissues and give riseto metastases. Adenocarcinomas are carcinomas derived from glandulartissue, or from tissues that form recognizable glandular structures.Another broad category of cancers includes sarcomas, which are tumorswhose cells are embedded in a fibrillar or homogeneous substance, likeembryonic connective tissue. The invention also enables treatments ofcancer of the myeloid or lymphoid systems, including leukemias, such asCLL, myelomas, such as multiple myeloma, lymphomas, and other cancersthat typically are not present as a tumor mass, but are distributed inthe vascular or lymphoreticular systems.

Cancers that may be treated using the compounds described hereininclude, without limitation, brain cancer, bone cancer, epithelial cellderived neoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer, stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,cervical cancer, lung cancer, breast cancer, skin cancer such assquamous cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body.

The activity of compounds of Formula I against various cancers can betested using assays known in the art, e.g., MTT assay to cancer celllines in vitro and animal tumor models—see, for example, Romijn et al.,1988 Prostate 12:99-110.

Cancers amenable to treatment with the compounds of the inventioninclude those mentioned above and those mediated by β-catenin. Exemplarycancers would include those having mutations in APC, the wnt/fzdsignaling pathway, axin and/or β-catenin resulting in β-cateninderegulation and a subsequent increase in free β-catenin in thecytoplasm and nucleus.

The identification of cancers mediated by β-catenin can be determinedusing a variety of techniques known in the art. For example, theexpression of wnt and/or fzd RNA can be measured in cancer cells andcompared to normal cells as described in International Publications Nos.WO 02/092635 and WO 02/088081 (both incorporated herein by reference intheir entireties). Cancers that overexpress wnt and/or fzd would beexpected to have deregulated β-catenin.

Deregulation of β-catenin can also be shown by analyzing the subcellularlocalization of β-catenin, e.g., cytoplasmic, nuclear and/or plasmamembrane in cancer cells as compared to normal cells of the same type.Such characterization can be done using techniques know in the artincluding immunohistochemistry, confocal microscopy, and immunoblotanalysis.

Samples for β-catenin analysis can be obtained using standard proceduresknow to those of skill in the art and include generally known biopsymethods including fine-needle aspiration, surgical biopsy, andcore-needle biopsy. Samples for analysis can also be fixed and embeddedin such materials as paraffin.

For a review of immunological and immunoassay procedures in general, seeStites et al. (eds.) (1991) Basic and Clinical Immunology (7th ed.).Immunoassays to detect β-catenin can be performed in any of severalconfigurations, which are reviewed extensively in Maggio (ed.) (1980)Enzyme Immunoassay CRC Press, Boca Raton, Fla.; Tijan (1985) “Practiceand Theory of Enzyme Immunoassays,” Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B. V.,Amsterdam; and Harlow and Lane Antibodies, A Laboratory Manual, supra,each of which is incorporated herein by reference. See also Chan (ed.)(1987) Immunoassay: A Practical Guide Academic Press, Orlando, Fla.;Price et al. (eds.) (1997) Principles and Practice of Immunoassay(2^(nd) ed), Groves Dictionaries, Inc.; Boenisch (ed.) (2001) HandbookImmunochemical Staining Methods DAKO Corp. Carpinteria, Calif., USA; andNgo (ed.). (1988) Non-isotopic Immunoassays Plenum Press, NY; allincorporated herein by reference.

In general, immunoassay design considerations include preparation ofantibodies (e.g., monoclonal or polyclonal) having sufficientlyhigh-binding specificity for their antigen so the specifically boundantibody-antigen complex can be distinguished reliably from nonspecificinteractions. Polyclonal and monoclonal antibodies that detect β-cateninare known in the art and are commercially available, e.g., Upstate CellSignaling Solutions, Charlottesville, Va.—catalogue nos. 06-734; 05-601;and 05-482.

Western blot analysis can be used to quantitate the amount of β-cateninprotein in a sample. Electrophoresis is carried out, e.g., on a tissuesample suspected of containing the protein. Following electrophoresis toseparate the proteins, and transfer of the proteins to a suitable solidsupport such as a nitrocellulose filter, the solid support is incubatedwith an antibody reactive with the denatured protein. This antibody maybe labeled, or alternatively may be it may be detected by subsequentincubation with a second labeled antibody that binds the primaryantibody.

A preferred method for identifying cancers that have deregulatedβ-catenin is immunohistochemistry (IHC). Immunohistochemistry allows forthe evaluation of micro-anatomical detail and heterogeneity in tissuesand tumors. Immunohistochemistry is advantageous over other methods ofanalyses because it is the only method that can directly localizeproteins to individual cell types and specific cell locations, e.g.,plasma membrane, cytoplasm, and/or nucleus. Differences among geneexpression of normal and tumor tissue can be detected whilesimultaneously noting the changes in cell number and composition. Incontrast, techniques, such as Western blotting require the use of cellextracts; therefore, a possibility exists of contamination of differentcell types. For IHC, a primary β-catenin antibody that recognizesβ-catenin protein is introduced to a biological specimen. Afterincubation with the primary antibody, a wash can be performed to removeunbound antibody. Then, a secondary antibody, directed against theprimary antibody and labeled with an enzyme, can be incubated with thebiological specimen. During incubation, the secondary antibody will bindto the primary antibody. Alternatively, the second antibody may lack alabel, but it may, in turn, be bound by a labeled third antibodyspecific to antibodies of the species from which the second antibody isderived.

The primary antibody can be labeled with an enzyme thus eliminating theneed for a second antibody. Alternatively, the labeled β-cateninantibody can be labeled with biotin rather than an enzyme. Then, in anadditional step, enzyme-labeled avidin or streptavidin is introduced tothe sample and allowed to bind to the biotinylated antibody.

For immunohistochemistry, the tissue sample may be fresh or frozen ormay be embedded, for example, in paraffin or other waxes,nitrocellulose, carbowax (also known as water soluble polyethyleneglycol (see, Gao ed. (1993) “Polyethylene Glycol as an Embedment forMicroscopy and Histochemistry,” CRC Press, Inc. Boca Raton, Fla.),plastic, including resins such as acrylic and epoxy resins, or OCTembedded frozen blocks. Preferably, the samples are embedded in paraffinor other waxes, nictrocellulose, carbowax, or plastic. The samples canbe fixed with a preservative, such as formalin, for example.

Samples for immunohistochemistry can be obtained from surgical biopsies,fine-needle biopsies, fine-needle aspiration biopsies, core-needlebiopsies, effusions from body cavities, such as the abdominal cavity,the pleural cavities and the pericardial cavity, and cells collectedfrom other bodily fluids, such as blood and urine and the like. Methodsof obtaining such samples are known in the art. For example, an effusionsample can be collected by puncturing the chest wall or abdominal wallwith a needle and evacuating the fluid. Samples from fine-needleaspirations, effusions or other bodily fluids can be spun onto slidesusing conventional centrifugation or Cytospin® (Shandon, Runcorn, U.K.)or smeared onto an appropriate slide for staining and/or fixation. Cellblocks can also be prepared from such samples by concentrating the cellscontained therein. For example, cells can be concentrated, e.g., bycentrifugation. After concentration, the cells can be fixed in asuitable fixing agent, such as formalin or alcohol and then embeddedinto paraffin or other suitable material as done for tissue in surgicalpathology. Concentrated cells can also be processed for ThinPrep®preparation using, for example, a Cytyc Thin Prep processor (Cytyc CorpBoxborough, Mass.).

Yet another technique for detecting β-catenin is Flow Cytometry (FACS).The theory of Flow Cytometry is discussed in Ormerod (ed) FlowCytometry: A Practical Approach (IRL Press, Oxford. 1994); Shapiro,Practical Flow Cytometry. 3rd Edition; (Alan R Liss, Inc.). Givan, FlowCytometry. First Principles (Wiley-Liss, New York, 1992.); Robinson(ed.) Handbook of Flow Cytometry Methods. (Wiley-Liss, New York, 1993)FACs provides the means of scanning individual cells for the presence ofderegulated β-catenin.

Antibodies reactive with a particular protein can also be measured by avariety of immunoassay methods, as discussed herein. For reviews ofimmunological and immunoassay procedures applicable to the measurementof antibodies by immunoassay techniques, see, e.g., Stites and Terr(eds.) Basic and Clinical Immunology (7th ed.) supra; Maggio (ed.)Enzyme Immunoassay, supra; and Harlow and Lane Antibodies, A LaboratoryManual, supra.

Techniques for determining β-catenin localization in cells usingimmunoassays are known in the art, for example, see Wakita et al. 2001Cancer Res. 61:854-858; Carayol et al. 2002 Am J. Respir Cell Mol. Biol.26:341-347; Lim et al 2002 Oncology Reports 9:915-928; and Sakai et al.2002 Int. J. Oncology 21:547-552; all incorporated herein by reference.

Other Conditions and Diseases

Other conditions and disease processes amenable to treatment with thecompounds described herein include, e.g., benign prostatic hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, fibrosis which occurs with radiation therapy,arthritis, psoriasis, glomerulonephritis, restenosis followingangioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections; and defective apoptosis-associated conditions,such as cancers (including, but not limited to, those types mentionedherein above), viral infections (including, but not limited to, HIV,human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus,Sindbis virus and adenovirus), prevention of AIDS development inHIV-infected individuals, autoimmune diseases (including, but notlimited to, systemic lupus erythematosus, rheumatoid arthritis,psoriasis, autoimmune mediated glomerulonephritis, inflammatory boweldisease and autoimmune diabetes mellitus), neurodegenerative disorders(including, but not limited to, Alzheimer's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-relateddementia, spinal muscular atrophy and cerebellar degeneration),myelodysplastic syndromes, aplastic anemia, ischemic injury associatedwith myocardial infarctions, stroke and reperfusion injury, arrhythmia,atherosclerosis, toxin-induced or alcohol related liver diseases,hematological diseases (including, but not limited to, chronic anemiaand aplastic anemia), degenerative diseases of the musculoskeletalsystem (including, but not limited to, osteroporosis and arthritis),aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis,schizophrenia, kidney diseases, abnormal angiogenesis, and cancer pain.

Compounds that inhibit uncontrolled or abnormal angiogenesis are usefulfor treatment of neoplasia, including metastasis; opthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including infantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the female reproductivesystem such as endometriosis.

Preparation of Compounds of the Invention

Compounds of the present invention may be synthesized using standardsynthetic techniques known to those of skill in the art or using methodsknown in the art in combination with methods described herein. See,e.g., March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Careyand Sundberg, ADVANCED ORGANIC CHEMISTRY 3^(rd) Ed., Vols. A and B(Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 2^(nd) Ed. (Wiley 1991). General methods for the preparationof compound as disclosed herein may be derived from known reactions inthe field, and the reactions may be modified by the use of appropriatereagents and conditions, as would be recognized by the skilled person,for the introduction of the various moieties found in the formulae asprovided herein.

Selected examples of covalent linkages and precursor functional groupswhich yield them are given in the Table entitled “Examples of CovalentLinkages and Precursors Thereof.” Precursor functional groups are shownas electrophilic groups and nucleophilic groups. The functional group onthe organic substance may be attached directly, or attached via anyuseful spacer or linker as defined below.

Examples of Covalent Linkages and Precursors Thereof

Covalent Linkage Product Electrophile Nucleophile Carboxamides Activatedesters amines/anilines Carboxamides acyl azides amines/anilinesCarboxamides acyl halides amines/anilines Esters acyl halidesalcohols/phenols Esters acyl nitriles alcohols/phenols Carboxamides acylnitriles amines/anilines Imines Aldehydes amines/anilines Hydrazonesaldehydes or ketones Hydrazines Oximes aldehydes or ketonesHydroxylamines Alkyl amines alkyl halides amines/anilines Esters alkylhalides carboxylic acids Thioethers alkyl halides Thiols Ethers alkylhalides alcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols Hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

In general, carbon electrophiles are susceptible to attack bycomplementary nucleophiles, including carbon nucleophiles, wherein anattacking nucleophile brings an electron pair to the carbon electrophilein order to form a new bond between the nucleophile and the carbonelectrophile.

Suitable carbon nucleophiles include, but are not limited to alkyl,alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-,alkenyl, aryl- and alkynyl-tin reagents (organostannanes), alkyl-,alkenyl-, aryl- and alkynyl-borane reagents (organoboranes andorganoboronates); these carbon nucleophiles have the advantage of beingkinetically stable in water or polar organic solvents. Other carbonnucleophiles include phosphorus ylids, enol and enolate reagents; thesecarbon nucleophiles have the advantage of being relatively easy togenerate from precursors well known to those skilled in the art ofsynthetic organic chemistry. Carbon nucleophiles, when used inconjunction with carbon electrophiles, engender new carbon-carbon bondsbetween the carbon nucleophile and carbon electrophile.

Non-carbon nucleophiles suitable for coupling to carbon electrophilesinclude but are not limited to primary and secondary amines, thiols,thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides,and the like. These non-carbon nucleophiles, when used in conjunctionwith carbon electrophiles, typically generate heteroatom linkages(C—X—C), wherein X is a hetereoatom, e.g, oxygen or nitrogen.

The term “protecting group” refers to chemical moieties that block someor all reactive moieties and prevent such groups from participating inchemical reactions until the protective group is removed. It ispreferred that each protective group be removable by a different means.Protective groups that are cleaved under totally disparate reactionconditions fulfill the requirement of differential removal. Protectivegroups can be removed by acid, base, and hydrogenolysis. Groups such astrityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labileand may be used to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and Fmoc groups, which are base labile. Carboxylicacid and hydroxy reactive moieties may be blocked with base labilegroups such as, without limitation, methyl, ethyl, and acetyl in thepresence of amines blocked with acid labile groups such as t-butylcarbamate or with carbamates that are both acid and base stable buthydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester derivatives asexemplified herein, or they may be blocked with oxidatively-removableprotective groups such as 2,4-dimethoxybenzyl, while co-existing aminogroups may be blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd₀-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups are described in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y.,1999, which is incorporated herein by reference in its entirety.

In various embodiments, the compounds of the present invention can beprepared according to the following reaction schemes and examples, ormodifications thereof. Starting materials can be purchased or made fromprocedures known in the art or as illustrated. In these reactions, oneskilled in the art can make use of variations that are not described ingreater detail. Other methods for preparing compounds of the inventionwill be readily apparent to the person of ordinary skill in the art inlight of the following reaction schemes and examples. For example, thesynthesis of non-exemplified compounds according to the invention may besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by changingto other suitable reagents known in the art, or by making routinemodifications of reaction conditions. Alternatively, other reactionsdisclosed herein or generally known in the art will be recognized ashaving applicability for preparing other compounds of the invention.Unless otherwise indicated, the variables are as defined above.

The abbreviations employed throughout the application have the followingmeaning unless otherwise indicated: EtOH: ethyl alcohol; NH₂OH.HCl:hydroxylamine; CCl₃CH(OH)₂: chloral hydrate; H₂SO₄: sulfuric acid;LiBH₄: lithium borohydride; ClCOCOCl: oxalyl chloride; HCl: Hydrochloricacid; NaOH: sodium hydroxide; BF₃.Et₂O: boron trifluoride etherate;CH₂Cl₂: dichloromethane; [R]: partial reduction.

General Scheme 1A shows the preparation of pyranoindol-1-yl alcoholsfrom starting material 1.

In General Scheme 1, 1,3,4,9-tetrahydro-pyrano[3,4-b]indole of thisinvention may be prepared by techniques well known to those skilled inthe art of organic synthesis. The substituted tryptophols (VI) may beprepared by the appropriate segment of the pathway illustrated inGeneral Scheme 1A, starting with an aniline (I), an isatin (III), or anindole (IV). The suitable starting materials are commercially availableanilines with the desired R or may be readily prepared. The aniline maybe converted into a corresponding isatin (III) by treatment of anilinewith chloral hydrate and hydroxylamine, followed by heating withsulfuric acid. The indole (IV) may be obtained by reduction of isatinwith lithium borohydride or other reducing agents. The tryptophol (VI)may be prepared by acylation at 3-position of indole (IV) with asuitable reagent, e.g., oxalyl chloride, followed by reduction ofglyoxylate (V) with lithium borohydride. The substituted tryptopholes(VI) may be condensed with an appropriate ketone or aldehyde, in thepresence of an acid catalyst, to provide1,3,4,9-tetrahydro-pyrano[3,4-b]indole (VII). After the ester (VII) isreduced by an appropriate reducing reagent, e.g., lithium borohydride,the title compounds (IX) may be prepared from (VIII) by displacement ofthe halogen with an appropriately activated Ar moiety. For example, inthe presence of an appropriate Pd(L)m catalyst, Ar-boronic acids may becoupled via a Suzuki reaction to give the title compounds (IX).Compounds (X) and (XI) may be prepared, via Heck reaction, from suitablealkyne and alkene precursors in the presence of an appropriate Pd(L)mcatalyst. The cis isomer of (XI) may also be prepared by partialreduction of (X) by hydrogenation over palladium on activated carbonthat has been treated with quinoline.

General Scheme 1B shows the preparation of pyranoindol-1-ylalkylsulfonamides from starting material 6.

Scheme 1B illustrates syntheses of the title compounds (XIII), (XIV), or(XV) wherein —(CH₂)nSO₂Y is substituted at 1-position of1,3,4,9-tetrahydro-pyrano[3,4-b]indole. The compounds (XIII) may beprepared by condensation of tryptophols (VI) with an appropriate ketoneor aldehyde bearing —SO₂Y in the presence of a suitable acid, followedby coupling reactions, which may be via Suzuki reaction with a suitableactivated Ar moiety in the presence of an appropriate Pd(L)m catalyst.Analogously, compounds (XIV) and (XV) may be prepared, via Heckreaction, from suitable alkyne and alkene in the presence of anappropriate Pd(L)m catalyst.

General Scheme 2 illustrates the additional embodiment wherein R₁₀ islower alkyl, lower alkenyl, lower alkynyl, or aryl. The nitrogen ofcompound (VII) may be alkylated with an appropriate alkyl halide in thepresence of a suitable base. After the ester is reduced to the alcohol(XVII) by a suitable reducing reagent, e.g., lithium borohydride, thetitle compounds (XVIII), (XIX), or (XX) may be prepared by couplingreactions, e.g., Suzuki reaction or Heck reaction.

General Scheme 3 illustrates the synthesis of compounds where R₇ issubstituted, R₉ is an isopropyl group, R₁ is ethyl, and Y-Z isethylalcohol.

General Scheme 4 illustrates the synthesis of pyranoindol-1-yl alcohols.

EXAMPLES Example 1 Synthesis of Compounds Compound 1:2-(1,8-Diethyl-6-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

1.A. Synthesis of N-(4-Bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide

To a suspension of 4-bromo-2-ethylaniline (50.0 g, 250 mmol) in water(1000 mL) was added concentrated hydrochloric acid (25 mL), sodiumsulfate (220 g), and hydroxylamine hydrochloride (56.25 g), followed byaddition of chloral hydrate (44.0 g). The reaction mixture was heated to90° C. using an oil bath for 1 hour. After cooling down to roomtemperature, it was extracted with ethyl acetate. Extract was dried overmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (31.1 g, 46% yield). ¹H NMR (DMSO-d₆) δ 12.24 (s, 1H),9.56 (s, 1H), 7.68 (s, 1H), 7.41 (m, 3H), 2.58 (q, 2H), 1.11 (t, 3H).

1.B. Synthesis of 5-Bromo-7-ethyl-1H-indole-2,3-dione

To a solution of sulfuric acid (100 mL) and water (10 mL) at 80° C. (oilbath) was added N-(4-bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide(61.0 g, 225 mmol) in small portions over 20 minutes. The reactionmixture was heated at 80° C. (oil bath) for 15 minutes. After cooling toroom temperature, ice-water (500 mL) was added and the mixture wasextracted with ethyl acetate. Extracts were washed with saturated sodiumbicarbonate solution, dried over magnesium sulfate, and concentratedunder reduced pressure to give the title compound (42.3 g, 74% yield).¹H NMR (DMSO-d₆) δ 8.87 (s, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 2.75 (q,2H), 1.44 (t, 3H).

1.C. Synthesis of (5-Bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethylester

To a solution of 5-bromo-7-ethyl-1H-indole-2,3-dione (36.g, 144 mmol) intetrahydrofuran (120 mL) at room temperature was dropped a 2.0 Msolution of lithium borohydride in tetrahydrofuran. The reaction mixturewas stirred at 90° C. (oil bath) for 5 hours. After cooling down to roomtemperature, it was quenched with 5% hydrochloric acid solution untilthe excess lithium borohydride was destroyed. To the mixture was addedsaturated sodium bicarbonate solution (300 mL) and extracted with ethylacetate. Extracts were dried over magnesium sulfate and concentratedunder reduced pressure to give the crude product of5-bromo-7-ethyl-1H-indole, which went to next reaction without furtherpurification.

To a solution of 5-bromo-7-ethyl-1H-indole in ethyl ether (400 mL) atroom temperature under nitrogen was added a 2.0 M solution of oxalylchloride in dichloromethane. After the reaction mixture was stirred atroom temperature for 6 hours, the solvents were removed under reducepressure. To the residue was added ethyl alcohol (400 mL) and stirred atroom temperature overnight. After ethyl alcohol was removed under reducepressure, to the residue was added saturated sodium bicarbonate solution(300 mL) and extracted with ethyl acetate. Extract was dried overmagnesium sulfate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel, 30-50% ethylacetate/hexane) to give the title compound (14.5 g, 31% yield). ES-MS(m/z) 324 [M+1]⁺, 322 [M−1]⁻.

1.D. Synthesis of(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

To a solution of (5-bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethylester (1.55 g, 4.8 mmol) in tetrahydrofuran at room temperature undernitrogen was dropped a 2.0 M solution of lithium borohydride intetrahydrofuran. The reaction mixture was heated at 90° C. oil bath for5 hours. After cooling to room temperature, it was quenched with 5%hydrochloric acid solution until the excess lithium borohydride wasdestroyed. To the mixture was added saturated sodium bicarbonatesolution and extracted with ethyl acetate. Extracts were dried overmagnesium sulfate and concentrated under reduced pressure to give thecrude product of 2-(5-bromo-7-ethyl-1H-indol-3-yl)-ethanol, which wentto the next reaction without further purification.

To a solution of 2-(5-bromo-7-ethyl-1H-indol-3-yl)-ethanol indichloromethane at room temperature under nitrogen was added borontrifluoride diethyl etherate (0.809 g, 5.7 mmol), followed by ethylpropionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirredat room temperature for 5 hours. It was quenched with saturated sodiumbicarbonate solution and extracted with dichloromethane. The extract wasdried over magnesium sulfate and concentrated under reduced pressure.The crude product was purified by column chromatography (silica gel,15-20% ethyl acetate/hexane) to give the title compound (0.994 g, 53%yield). ES-MS (m/z) 394 [M+1]⁺, 392 [M−1]⁻.

1.E. Synthesis of2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

To a solution of(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester (5.2 g, 13.2 mmol) in tetrahydrofuran at roomtemperature under nitrogen was dropped a 2.0 M solution of lithiumborohydride in tetrahydrofuran. The reaction mixture was heated at 90°C. (oil bath) for 5 hours. After cooling to room temperature, it wasquenched with 5% hydrochloric acid solution until the excess lithiumborohydride was destroyed. Water was added and the mixture extractedwith ethyl acetate. Extracts were dried over magnesium sulfate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel, 50% ethyl acetate/hexane) to give thetitle compound (3.80 g, 82% yield). ¹H NMR (CDCl₃) δ 8.07 (s, 1H), 7.64(d, 1H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87(dt, 1H), 2.76 (t, br, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H),1.49 (t, 3H), 1.08 (t, 3H). ES-MS (m/z) 352 [M+1]⁺, 350 [M−1]⁻.

1.F. Synthesis of2-(1,8-Diethyl-6-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

To a solution of2-(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol(3.8 g, 10.8 mmol) in ethylene glycol dimethyl ether (50 mL) was addedpotassium phosphate (6.37 g, 30 mmol), phenylboronic acid (1.83 g, 15mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane. The reaction mixture was heated at 90° C.(oil bath) overnight. It was quenched with water and extracted withethyl acetate. Extracts were dried over magnesium sulfate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel, 50% ethyl acetate/hexane, followed bySephadex LH-20, 50% chloroform/hexane) to give the title compound (0.75g, 20% yield). ¹H NMR (CDCl₃) δ 7.77 (s, 1H), 7.66 (d, 1H), 7.63 (m,1H), 7.56 (d, 1H), 7.44 (m, 3H), 7.32 (m, 1H), 4.06 (m, 2H), 3.72 (m,3H), 2.91 (m, 3H), 2.81 (dt, 1H), 2.65 (dd, 1H), 2.20 (m, 1H), 2.07 (m,2H), 1.40 (t, 3H), 0.95 (t, 3H). ES-MS (m/z) 348 [M−1]−.

Compound 2:2-[1,8-Diethyl-6-(4-methoxy-phenyl)-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 4-methoxyphenylboronic acid in step 1.F.

Compound 3:2-[1,8-Diethyl-6-(3-trifluoromethoxy-phenyl)-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 3-trifluoromethoxyphenylboronic acid in step 1.F.

Compound 4:2-[1,8-Diethyl-6-(2-trifluoromethyl-phenyl)-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared as described in Example 1, except using2-trifluoromethylphenylboronic acid in step 1.F.

Compound 5:2-[6-(2,4-Difluoro-phenyl)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 2,4-difluorophenylboronic acid in step 1.F.

Compound 6:2-(1,8-Diethyl-6-pyridin-4-yl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to Example 1,except using pyridine-4-boronic acid in step 1.F.

Compound 8:2-[6-(3-Amino-phenyl)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 3-aminophenylboronic acid in step 1.F.

Compound 10:2-[6-(3,4-Difluoro-phenyl)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 3,4-difluorophenylboronic acid in step 1.F.

Compound 11:2-[6-(5-Chloro-thiophen-2-yl)-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using 5-chloro-2-thiopheneboronic acid in step 1.F.

Compound 12:2-(1-Ethyl-6-isopropyl-8-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

12.A. Synthesis ofN-(2-Bromo-4-isopropyl-phenyl)-2-hydroximino-acetoamide

The title compound is prepared in a manner analogous to Example 1,except using 2-bromo 4-aminoaniline in step 1.A.

12.B. Synthesis of 7-Bromo-5-isopropyl-1H-indole-2,3-dione

The title compound is prepared in a manner analogous to Example 1,except using N-(2-bromo-4-isopropyl-phenyl)-2-hydroximino-acetoamide instep 1.B.

12.C. Synthesis of (7-Bromo-5-isopropyl-1H-indol-3-yl)-oxo-acetic acidethyl ester

The title compound is prepared in a manner analogous to Example 1,except using 7-bromo-5-isopropyl-1H-indole-2,3-dione in step 1.C.

12.D. Synthesis of(8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

The title compound is prepared in a manner analogous to Example 1,except using (7-bromo-5-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethylester in step 1.D.

12.E. Synthesis of2-(8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to Example 1,except using(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester in step 1.E.

12.F. Synthesis of2-(1-Ethyl-6-isopropyl-8-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanolin step 1.F.

Compound 13:2-[8-(3-Cyano-phenyl)-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanoland 3-cyanophenylboronic acid in step 1.F.

Compound 14:2-[8-(5-Bromo-2-methoxy-phenyl)-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanoland 2-bromo-3-methoxyphenylboronic acid in step 1.F.

Compound 15:2-[1′-Ethyl-8-(2-fluoro-biphenyl-4-yl)-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1′-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanoland 2-fluorobiphenyl-4-boronic acid in step 1.F.

Compound 16:4-[1′-Ethyl-1′-(2-hydroxy-ethyl)-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-8-yl]-benzoicacid

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1′-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1′-yl)-ethanoland 4-carboxylphenylboronic acid in step 1.F.

Compound 17:3-[1′-Ethyl-1′-(2-hydroxy-ethyl)-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-8-yl]-benzaldehyde

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.

Compound 18:2-[8-(3,5-Dimethyl-phenyl)-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanoland 3,5-dimethylphenylboronic acid in step 1.F.

Compound 19:2-(8-Dibenzofuran-3-yl-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to Example 1,except using2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanoland 4-dibenzofuranboronic acid in step 1.F.

Compound 20:2-(1-Ethyl-6-isopropyl-8-styryl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

20.A. Synthesis of2-(1-Ethyl-6-isopropyl-8-styryl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared according to the following procedure. Tosolution of2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol(1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is addedtriethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0mmol), and tri(dibenzylideneacetone)dipalladium (0) (0.1 mmol). Thereaction mixture is heated at 90° C. (oil bath) overnight. It isquenched with water and extracted with ethyl acetate. Extracts are driedover magnesium sulfate and concentrated under reduced pressure. Thechromatography (silica gel) gives the title compound.

Compound 21:2-(1-Ethyl-6-isopropyl-8-phenylethynyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to Example 20.A,except using phenylacetylene.

Compound 22:(1-Ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound is prepared in a manner analogous to the procedureoutlined below:

22.A. Synthesis of(1-Ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethylester

A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate(1.730 g, 12 mmol), and p-toluenesulfonic acid monohydrate (0.20 g) inbenzene (70 mL) was heated to reflux for 5 hours. It was quenched withethyl acetate and washed with saturated sodium bicarbonate. The organiclayer was dried over magnesium sulfate, evaporated to dryness. Flashchromatography on silica gel provided 1.943 g (68%) of the titlecompound as a solid. mp<80° C. ¹H NMR (300 MHz, CDCl₃) δ 9.06 (br, 1H),7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H),4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H),2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI (+) MSm/e=288 (MH⁺), ESI (−) MS m/e=286 (MH⁻).

22.B. Synthesis of(1-Ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid

To a solution of(1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethylester (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithiumhydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mL). The mixturewas stirred at room temperature overnight. It was neutralized with 5%HCl solution and extracted with ethyl acetate. The extracts were washedwith brine, dried over magnesium sulfate, and evaporated to dryness.Flash chromatography on silica gel provided 0.954 g (42%) of the titlecompound as a solid. mp. 135-136° C. ¹H NMR (500 MHz, CDCl₃) δ 10.0 (br,1H), 8.55 (br, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.18 (t, 1H), 7.12 (t,1H), 4.12 (m, 1H), 4.06 (m, 1H), 3.01 (d, 1H), 2.99 (d, 1H), 2.85 (m,2H), 2.10 (m, 1H), 2.03 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=260 (MH⁺),ESI (−) MS m/e=258 (MH⁻).

22.C. Synthesis of(1-Ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

To solution of(1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminumhydride (0.114 g, 3.0 mmol) in several small portions. The mixture wasstirred at room temperature for 6 hours. It was quenched with ethylacetate carefully and washed with water. The organic layer was driedover magnesium sulfate and evaporated to dryness. Flash chromatographyon silica gel provided 0.389 g (79%) of the title compound as an oil. ¹HNMR (500 MHz, CDCl₃) δ 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18(td, 1H), 7.13 (td, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.70 (m, 1H), 3.64(m, 1H), 2.89 (m, 1H), 2.77 (dt, 1H), 2.71 (br, 1H), 2.20 (m, 1H), 2.05(m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=246(MH⁺), ESI (−) MS m/e=244 (MH⁻).

Compound 23:2-(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

23.A. Synthesis of(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

The title compound was synthesized in a manner analogous to step 22,using 5-methoxytrypotophol as the 3-indolethanol component in step 22.A.¹H NMR (300 MHz, CDCl₃) δ 8.93 (br, 1H), 7.25 (d, 1H), 6.95 (d, 1H),6.90 (dd, 1H), 4.17 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 3.86 (s, 3H),2.99 (d, 1H), 2.90 (d, 1H), 2.74 (m, 2H), 2.12 (m, 1H), 2.00 (m, 1H),1.27 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=318 (MH⁺), ESI (−) MS m/e=316(MH⁻).

23.B. Synthesis of(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

The title compound was synthesized in a manner analogous to step 22,using(1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component in step 22.B., afforded thetitle compound as a solid. mp. 169° C. ¹H NMR (300 MHz, CDCl₃) δ 8.38(br, 1H), 7.22 (d, 1H), 6.94 (d, 1H), 6.84 (dd, 1H), 4.08 (m, 2H), 3.85(s, 3H), 2.97 (m, 2H), 2.81 (m, 2H), 2.02 (m, 2H), 0.85 (t, 3H); ESI (+)MS m/e=290 (MH⁺), ESI (−) MS m/e=288 (MH⁻).

23.C. Synthesis of2-(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound was synthesized in a manner analogous to step 22,using(1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component in step 22.C., afforded the titlecompound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.71 (br, 1H), 7.22 (d,1H), 6.97 (d, 1H), 6.83 (dd, 1H), 4.08 (m, 1H), 4.00 (m, 1H), 3.86 (s,3H), 3.69 (m, 1H), 3.64 (m, 1H), 2.85 (m, 1H), 2.73 (dt, 1H), 2.19 (m,1H), 2.05 (br, 1H), 2.03 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.93 (t,3H); ESI (+) MS m/e=276 (MH⁺), ESI (−) MS m/e=274 (MH⁻).

Compound 24:2-(1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

24.A. Synthesis of 2-(5-Methyl-1H-indol-3-yl)-ethanol

To a suspension of 4-methylphenylhydrazine hydrochloride (2.50 g, 15.7mmol) in 1,4-dioxane (25 mL) and water (1.5 mL) was dropped neat2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixturewas heated at 95° C. for 4 hours. After cooling to room temperature, itwas poured into ethyl ether, dried over magnesium sulfate, evaporated todryness. Flash chromatography on silica gel provided 0.485 g (18%) ofthe title compound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (br, 1H),7.41 (s, 1H), 7.27 (d, 1H), 7.05 (m, 2H), 3.90 (dd, 2H), 3.01 (t, 2H),2.46 (s, 3H), 1.50 (t, br, 1H).

24.B. Synthesis of(1-Ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol)in dichloromethane (10 mL) was added boron trifluoride diethyl etherate(0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5mmol). The mixture was stirred at room temperature for 5 hours. It wasquenched with saturated sodium bicarbonate solution and extracted withdichloromethane. The organic layer was dried over magnesium sulfate andevaporated to dryness. Flash chromatography on silica gel provided 0.421g (52%) of the title compound as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.90(br, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 4.16 (m, 2H), 4.03(m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73(m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80(t, 3H); ESI (−) MS m/e=300 (MH⁻).

24.C. Synthesis of(1-Ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

The title compound was synthesized in a manner analogous to step 22.B.,using(1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. mp. 158-159° C. ¹H NMR (500 MHz, CDCl₃) δ 9.70 (br, 1H), 8.33(br, 1H), 7.29 (s, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 4.10 (m, 1H), 4.05(m, 1H), 2.99 (d, 1H), 2.98 (d, 1H), 2.81 (q, 2H), 2.44 (s, 3H), 2.07(m, 1H), 2.01 (m, 1H), 0.85 (t, 3H); ESI (+) MS m/e=274 (MH⁺), ESI (−)MS m/e=272 (MH⁻).

24.D. Synthesis of2-(1-Ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

The title compound was synthesized in a manner analogous to step 22.C.,using(1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. mp. 114-115° C. ¹H NMR (500 MHz, CDCl₃) δ 7.70 (br, 1H), 7.30 (s,1H), 7.21 (d, 1H), 7.00 (dd, 1H), 4.06 (m, 1H), 3.97 (m, 1H), 3.67 (m,1H), 3.62 (m, 1H), 2.84 (m, 1H), 2.73 (m, 1H), 2.71 (br, 1H), 2.45 (s,3H), 2.17 (m, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 0.92 (t,3H); ESI (+) MS m/e=260 (MH⁺), ESI (−) MS m/e=258 (MH⁻).

Compound 25:2-(1-Ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

25.A. Synthesis of 2-(7-Methyl-1H-indol-3-yl)-ethanol.

Following the procedure of example 24.A. except using2-methylphenylhydrazine hydrochloride as the hydrazine componentafforded the title compound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.97(br, 1H), 7.49 (d, 1H), 7.11 (d, 1H), 7.07 (t, 1H), 7.03 (d, 1H), 3.91(t, 2H and br, 1H), 3.04 (t, 2H), 2.49 (s, 3H).

25.B. Synthesis of(1-Ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 23.B. except using2-(7-methyl-1H-indol-3-yl)-ethanol as the 3-indolethanol componentafforded the title compound as solid. mp. 77-78° C. ¹H NMR (500 MHz,CDCl₃) δ 9.04 (br, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.97 (d, 1H), 4.19(m, 2H), 4.04 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.90 (d, 1H), 2.81(m, 1H), 2.75 (dt, 1H), 2.49 (s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.27(t, 3H), 0.83 (t, 3H); ESI (−) MS m/e=300 (MH⁻).

25.C. Synthesis of2-(1-Ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol.

Following the procedure of example 22.C. except using(1-ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the carboxylic acid component afforded the titlecompound as a solid. mp. 68° C. ¹H NMR (500 MHz, CDCl₃) δ 7.68 (br, 1H),7.37 (d, 1H), 7.05 (t, 1H), 6.98 (d, 1H), 4.06 (m, 1H), 3.98 (m, 1H),3.70 (m, 1H), 3.65 (m, 1H), 2.88 (m, 1H), 2.76 (t, 1H), 2.72 (m, 1H),2.47 (s, 3H), 2.21 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), 1.91 (m, 1H),0.94 (t, 3H); ESI (+) MS m/e=260 (MH⁺), ESI (−) MS m/e=258 (MH⁻).

Compound 26:2-(1-Ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

26.A. Synthesis of 2-(7-Fluoro-1H-indol-3-yl)-ethanol

Following the procedure of example 24.A. except using2-fluorophenylhydrazine hydrochloride as the hydrazine componentafforded the title compound as an oil.

26.B. Synthesis of(1-Ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of 24.B. except using2-(7-fluoro-1H-indol-3-yl)-ethanol as the 3-indolethanol componentafforded the title compound as an oil.

26.C. Synthesis of2-(1-Ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the carboxylic acid component afforded the titlecompound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (br, 1H), 7.27 (d,1H), 7.02 (m, 1H), 6.89 (dd, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.71 (m,1H), 3.65 (m, 1H), 2.88 (m, 1H), 2.78 (dt, 1H), 2.76 (br, 1H), 2.22 (m,1H), 2.07 (m, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MSm/e=264 (MH⁺), ESI (−) MS m/e=262 (MH⁻).

Compound 27:2-(8-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

27.A. Synthesis of 2-(7-Chloro-1H-indol-3-yl)-ethanol

Following the procedure of 24.A. except using 2-chlorophenylhydrazinehydrochloride as the hydrazine component afforded the title compound asan oil. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (br, 1H), 7.52 (d, 1H), 7.21 (d,1H), 7.15 (d, 1H), 7.06 (t, 1H), 3.91 (t, 2H), 3.02 (t, 2H), 1.48 (br,1H).

27.B. Synthesis of(8-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of 24.B. except using2-(7-chloro-1H-indol-3-yl)-ethanol as the 3-indolethanol componentafforded the title compound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.28(br, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.02 (t, 1H), 4.18 (m, 2H), 4.05(m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.82 (m, 1H), 2.75(dt, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 1.27 (t, 3H), 0.84 (t, 3H); ESI(−) MS m/e=230 (MH⁻).

27.C. Synthesis of(8-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.81 (br, 1H), 7.40 (d, 1H), 7.17 (d,1H), 7.04 (t, 1H), 4.09 (m, 1H), 4.03 (m, 1H), 3.05 (d, 1H), 3.02 (d,1H), 2.82 (m, 2H), 2.13 (m, 1H), 2.06 (m, 1H), 0.88 (t, 3H); ESI (+) MSm/e=294 (MH⁺), ESI (−) MS m/e=292 (MH⁻).

27.D. Synthesis of2-(8-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.05 (br, 1H), 7.41 (d, 1H), 7.17 (d,1H), 7.05 (t, 1H), 4.07 (m, 1H), 4.00 (m, 1H), 3.72 (m, 1H), 3.67 (m,1H), 2.87 (m, 1H), 2.76 (dt, 1H), 2.70 (br, 1H), 2.23 (m, 1H), 2.03 (m,1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=280 (MH⁺), ESI (−) MSm/e=278 (MH⁻).

Compound 28:2-(8-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

28.A. Synthesis of 2-(7-Bromo-1H-indol-3-yl)-ethanol

Following the procedure of example 24.A. except using2-bromophenylhydrazine hydrochloride as the hydrazine component affordedthe title compound as an oil.

28.B. Synthesis of(8-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidethyl ester

Following the procedure of 24.B. except using2-(7-bromo-1H-indol-3-yl)-ethanol as the 3-indolethanol componentafforded the title compound as an oil.

28.C. Synthesis of2-(8-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

To a solution of(8-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidethyl ester (1.03 g, 2.8 mmol) in tetrahydrofuran at room temperaturewas added 2.0 M solution of lithium borohydride in tetrahydrofuran. Themixture was heated to reflux for 5 hours. It was quenched with 5% HClsolution, followed by saturated sodium bicarbonate. It was extractedwith ethyl acetate, extracts were dried over magnesium sulfate, and itwas evaporated to dryness. Crystallization with diethyl ether afforded0.682 g (75%) of the title compound as a solid. ¹H NMR (500 MHz, CDCl₃)δ 8.01 (br, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 7.00 (t, 1H), 4.07 (m, 1H),3.99 (m, 1H), 3.72 (m, 1H), 3.67 (m, 1H), 2.87 (m, 1H), 2.75 (dt, 1H),2.68 (dd, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H),0.94 (t, 3H); ESI (+) MS m/e=324 (MH⁺), ESI (−) MS m/e=322 (MH⁻).

Compound 29:2-(8-Ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

29.A. Synthesis of 2-(7-Ethyl-1H-indol-3-yl)-ethanol

Following the procedure of example 24.A. except using2-ethylphenylhydrazine hydrochloride as the hydrazine component affordedthe title compound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.05 (br, 1H),7.50 (d, 1H), 7.08 (m, 3H), 3.92 (m, 2H), 3.04 (m, 2H), 2.86 (m, 2H),2.06 (br, 1H), 1.35 (t, 3H); ESI (+) MS m/e=190 (MH⁺), ESI (−) MSm/e=188 (MH⁻).

29.B. Synthesis of(8-Ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 22.A. except using2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component andthe ethyl acetoacetate as ketone component afforded the title compoundas an oil. ¹H NMR (500 MHz, CDCl₃) δ 9.16 (br, 1H), 7.35 (d, 1H), 7.01(m, 2H), 4.17 (m, 2H), 4.02 (m, 2H), 2.85 (m, 6H), 1.57 (t, 3H), 1.36(t, 3H), 1.29 (t, 3H); ESI (+) MS m/e=302 (MH⁺), ESI (−) MS m/e=300(MH⁻).

29.C. Synthesis of(8-Ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 1, step (b) except using(8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ESI (−) MS m/e=272 (MH⁻).

29.D. Synthesis of2-(8-Ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.74 (br, 1H), 7.37 (d, 1H), 7.09 (m,1H), 7.03 (d, 1H), 4.12 (m, 1H), 3.98 (m, 1H), 3.70 (m, 2H), 2.92 (m,1H), 2.85 (m, 2H), 2.74 (m, 2H), 2.15 (m, 2H), 1.56 (s, 3H), 1.36 (t,3H); ESI (+) MS m/e=282 (MNa⁺), ESI (−) MS m/e=258 (MH⁻).

Compound 30:2-(8-Ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

30.A. Synthesis of(8-Ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 1, step (a) except using2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component andthe ethyl butyrylacetate as ketone component afforded the title compoundas a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.10 (br, 1H), 7.34 (d, 1H), 7.03(m, 2H), 4.17 (m, 2H), 4.02 (m, 1H), 3.92 (m, 1H), 2.99 (d, 1H), 2.84(m, 3H), 2.73 (dt, 1H), 2.09 (m, 1H), 1.96 (m, 1H), 1.35 (t, 3H), 1.26(t, 3H), 1.19 (m, 2H), 0.85 (t, 3H); ESI (+) MS m/e=330 (MH⁺), ESI (−)MS m/e=328 (MH⁻).

30.B. Synthesis of(8-Ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid.

30.C. Synthesis of2-(8-Ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (br, 1H), 7.36 (d, 1H), 7.09 (t,1H), 7.02 (m, 1H), 4.05 (m, 1H), 4.01 (m, 1H), 3.72 (m, 1H), 3.67 (m,1H), 2.85 (m, 2H), 2.76 (dt, 1H), 2.68 (br, 1H), 2.20 (m, 1H), 2.09 (m,1H), 1.90 (m, 2H), 1.48 (m, 1H), 1.36 (t, 3H), 1.32 (m, 1H), 0.91 (t,3H); ESI (+) MS m/e=288 (MH⁺), ESI (−) MS m/e=286 (MH⁻).

Compound 31:2-(8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

31A. Synthesis of(8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 22.A. except using2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component andethyl iso-butyrylacetate as ketone component afforded the title compoundas a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.12 (br, 1H), 7.36 (d, 1H), 7.07(m, 2H), 4.13 (m, 3H), 3.81 (m, 1H), 3.04 (q, 2H), 2.87 (m, 3H), 2.66(m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69(d, 3H).

31.B. Synthesis of(8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 24.B. except using(8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.70 (br, 1H), 8.55 (br, 1H), 7.36 (d,1H), 7.07 (dd, 1H), 7.01 (d, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 3.10 (q,2H), 2.82 (m, 4H), 2.52 (m, 1H), 1.32 (t, 3H), 1.06 (d, 3H), 0.82 (d,3H); ESI (+) MS m/e=302 (MH⁺), ESI (−) MS m/e=300 (MH⁻).

31.C. Synthesis of2-(8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.68 (br, 1H), 7.38 (d, 1H), 7.09 (dd,1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.87 (m, 3H), 2.77 (dt,1H), 2.68 (br, 1H), 2.32 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.35 (t,3H), 1.05 (d, 3H), 1.00 (d, 3H); ESI (+) MS m/e=288 (MH⁺), ESI (−) MSm/e=286 (MH⁻).

Compound 32:2-(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

32.A. Synthesis of(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 22.A. except using2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component andethyl benzoylacetate as ketone component afforded the title compound asa solid. ¹H NMR (500 MHz, CDCl₃) δ 10.05 (br, 1H), 7.42 (d, 1H), 7.28(m, 5H), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H), 3.43 (d, 1H), 3.22(d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI(−) MS m/e=362 (MH⁻).

32.B. Synthesis of(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.25 (br, 1H), 7.41 (d, 1H), 7.31 (m,5H), 7.10 (t, 1H), 7.06 (d, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.42 (d,1H), 3.22 (d, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.68 (m, 1H), 1.33 (t,3H); ESI (+) MS m/e=358 (MNa⁺). ESI (−) MS m/e=334 (MH⁻).

32.C. Synthesis of2-(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (br, 1H), 7.38 (m, 3H), 7.32 (m,3H), 7.12 (t, 1H), 7.08 (d, 1H), 4.12 (m, 2H), 3.99 (dd, 1H), 3.61 (ddd,1H), 3.01 (m, 1H), 2.94 (q, 2H), 2.61 (m, 2H), 2.47 (m, 1H), 1.39 (t,3H).

Compound 34:[8′-Ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indol)-4-yl]-methanol

34.A. Synthesis of8′-Ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indole)-4-carboxylicacid ethyl ester

Following the procedure of example 24.A. except using2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and4-oxo-cyclohexane carboxylic acid ethyl ester as ketone componentafforded the title compound as an oil. ESI (+) MS m/e=342 (MH⁺), ESI (−)MS m/e=340 (MH⁻).

34.B. Synthesis of8′-Ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indole)-4-carboxylicacid

Following the procedure of example 22.B. except using8′-ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indole)-4-carboxylicacid ethyl ester as the ester component afforded the title compound as asolid. ESI (+) MS m/e=314 (MH⁺), ESI (−) MS m/e=312 (MH⁻).

34.C. Synthesis of[8′-Ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indol)-4-yl]-methanol

Following the procedure of example 22.C. except using8′-ethyl-4′,9′-dihydro-3′H-spiro(cyclohexane-1,1′-pyrano[3,4-b]indole)-4-carboxylicacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.51 (br, 1H), 7.33 (d, 1H), 7.06 (t,1H), 7.00 (d, 1H), 3.97 (t, 2H), 3.54 (t, 2H), 2.84 (q, 2H), 2.78 (t,2H), 2.12 (br, 1H), 2.09 (m, t, 1H), 1.69 (m, 4H), 1.60 (m, 1H), 1.52(m, 3H), 1.35 (t, 3H); ESI (+) MS m/e=300 (MH⁺), ESI (−) MS m/e=298(MH⁻).

Compound 35:R-2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

35.A. Synthesis ofR-2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22, except usingR-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidas the carboxylic acid component in step 22.C. afforded the titlecompound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.74 (br, 1H), 7.37 (d,1H), 7.09 (t, 1H), 7.03 (d, 1H), 4.07 (m, 1H), 3.98 (m, 1H), 3.68 (m,2H), 2.86 (m, 3H), 2.76 (dt, 1H), 2.69 (br, t, 1H), 2.21 (m, 1H), 2.07(m, 1H), 2.00 (m, 1H), 1.91 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+)MS m/e=274 (MH⁺), ESI (−) MS m/e=272 (MH⁻).

Compound 36:2-(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

36.A. Synthesis of 2-Hydroxyimino-N-(2-isopropyl-phenyl)-acetamide

A mixture of 2-isopropylaniline (4.7 g, 35 mmol), Na₂SO₄ (30.0 g),concentrated hydrochloride (3 mL), chloral hydrate (6.5 g),hydroxylamine hydrochloride (8.00 g) in water (150 mL) was heated at 85°C. for 40 minutes. After cooling to room temperature, it was extractedwith ethyl acetate. The extracts were dried over magnesium sulfate andevaporated to dryness. Flash chromatography on silica gel provided 4.357g (54%) of the title compound as solid.

36.B. Synthesis of 7-Isopropyl-1H-indole-2,3-dione

To concentrated sulfuric acid at 80° C. was added2-hydroxyimino-N-(2-isopropyl-phenyl)-acetamide in several smallportions over 10 minutes. After addition it was heated at 80° C. for 30minutes., then poured into ice. Filtration, washing with water, anddrying under vacuum over P₂O₅ provided 2.974 g (84%) of the titlecompound as a solid. ESI (−) MS m/e=188 (MH⁻).

36.C. Synthesis of (7-Isopropyl-1H-indol-3-yl)-oxo-acetic acid ethylester

To a solution of 7-isopropyl-1H-indole-2,3-dione (2.97 g, 15.7 mmol) intetrahydrofuran (20 mL) was dropped 2.0 M solution of lithiumborohydride in tetrahydrofuran (15 mL, 30 mmol). The mixture was heatedat 90° C. for 4 hours. It was quenched with 5% HCl, followed bysaturated sodium bicarbonate. It was extracted with ethyl acetate. Theextracts were dried over magnesium sulfate and evaporated to dryness toprovide a crude 7-isopropyl-1H-indole. To a solution of the crude7-isopropyl-1H-indole in diethyl ether (40 mL) was dropped 2.0 Msolution of oxalyl chloride in dichloromethane (15 mL, 30 mmol). Afterstirring at room temperature for 5 hours, it was evaporated to dryness.Ethanol was added to the residue and it was stirred at room temperatureovernight. After the ethanol was evaporated, flash chromatography onsilica gel provided 0.972 g (24%) of the title compound as solid. ESI(−) MS m/e=258 (MH⁻).

36.D. Synthesis of(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

To a solution of (7-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester(0.97 g. 3.7 mmol) in tetrahydrofuran was added 2.0 M solution oflithium borohydride in tetrahydrofuran. The mixture was heated at 90° C.for 5 hours. It was quenched with 5% HCl, followed by saturated sodiumbicarbonate. It was extracted with ethyl acetate. The extracts weredried over magnesium sulfate and evaporated to dryness to provide acrude 2-(7-isopropyl-1H-indol-3-yl)-ethanol. ESI (+) MS m/e=204 (MH⁺),ESI (−) MS m/e=202 (MH⁻).

Following the procedure of example 24.B. except using2-(7-isopropyl-1H-indol-3-yl)-ethanol as the 3-indolethanol componentafforded the title compound as an oil. ESI (+) MS m/e=330 (MH⁺), ESI (−)MS m/e=328 (MH⁻).

36.E. Synthesis of(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. mp. 158-159° C. ¹H NMR (500 MHz, CDCl₃) δ 9.50 (br, 1H), 8.58(br, 1H), 7.36 (d, 1H), 7.08 (m, 2H), 4.09 (m, 1H), 4.04 (m, 1H), 3.20(m, 1H), 3.05 (d, 1H), 3.02 (d, 1H), 2.84 (m, 2H), 2.13 (m, 1H), 2.04(m, 1H), 1.38 (d, 3H), 1.35 (d, 3H), 0.88 (t, 3H); ESI (+) MS m/e=302(MH⁺), ESI (−) MS m/e=300 (MH⁻).

36.F. Synthesis of2-(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as aoil. ¹H NMR (500 MHz, CDCl₃) δ 7.78 (br, 1H), 7.36 (d, 1H), 7.11 (t,1H), 7.07 (d, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.71 (m, 2H), 3.20 (m,1H), 2.90 (m, 1H), 2.76 (dt, 1H), 2.65 (br, 1H), 2.22 (m, 1H), 2.06 (m,1H), 2.03 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 0.88 (t, 3H); ESI (+) MSm/e=288 (MH⁺), ESI (−) MS m/e=286 (MH⁻).

Compound 37:2-(1-Ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

37.A. Synthesis of 2-Hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide

Following the procedure of example 36.A. except using2-trifluoromethylaniline as the aniline component afforded the titlecompound as a solid.

37.B. Synthesis of 7-Trifluoromethyl-1H-indole-2,3-dione

Following the procedure of example 36.B. except using2-hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide as the acetamidecomponent afforded the title compound as a solid. ESI (−) MS m/e=214(MH⁻).

37.C. Synthesis of (7-Trifluoromethyl-1H-indol-3-yl)-oxo-acetic acidethyl ester

Following the procedure of example 36.C. except using7-trifluoromethyl-1H-indole-2,3-dione as the dione component affordedthe title compound as a solid.

37.D. Synthesis of2-(1-Ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 28.C. except using(1-ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.42 (br, 1H), 7.67 (d, 1H), 7.41 (d,1H), 7.18 (t, 1H), 4.07 (m, 1H), 4.00 (m, 1H), 3.71 (m, 2H), 2.89 (m,1H), 2.78 (dt, 1H), 2.64 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.02 (m,1H), 1.93 (m, 1H), 0.93 (t, 3H); ESI (+) MS m/e=314 (MH⁺), ESI (−) MSm/e=312 (MH⁻).

Compound 38:2-(5-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

38.A. Synthesis of (4-Chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.C. except using 4-chloro-1H-indoleas the indole component afforded the title compound as a solid.

38.B. Synthesis of5-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidethyl ester

Following the procedure of example 36.D. except using(4-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil. ¹H NMR (008-08) MS. ESI(+) MS m/e=322 (MH⁺), ESI (−) MS m/e=320 (MH⁻).

38.C. Synthesis of(5-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B except using(5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ESI (+) MS m/e=294 (MH⁺), ESI (−) MS m/e=292 (MH⁻).

38.D. Synthesis of2-(5-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (br, 1H), 7.20 (dd, 1H), 7.04 (m,2H), 4.05 (m, 1H), 3.97 (m, 1H), 3.68 (m, 2H), 3.16 (m, 2H), 2.19 (m,1H), 2.04 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (−) MSm/e=278 (MH⁻).

Compound 39:2-(1-Ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

39.A. Synthesis of (4-Fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.C. except using 4-fluoro-1H-indoleas the indole component afforded the title compound as a solid.

39.B. Synthesis of(1-Ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(4-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil. ESI (−) MS m/e=304(MH⁻).

39.C.(1-Ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(1-ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.70 (br, 1H), 8.75 (br, 1H), 7.06 (m,2H), 6.73 (dd, 1H), 4.08 (m, 1H), 4.04 (m, 1H), 3.00 (m, 4H), 2.10 (m,1H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=278 (MH⁺), ESI (−) MSm/e=276 (MH⁻).

39.D. Synthesis of2-(1-Ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (br, 1H), 7.08 (d, 1H), 7.04 (ddd,1H), 6.75 (dd, 1H), 4.04 (m, 1H), 3.98 (m, 1H), 3.67 (m, 2H), 3.04 (m,1H), 2.93 (m, 1H), 2.61 (br, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 2.01 (m,1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH⁺), ESI (−) MSm/e=262 (MH⁻).

Compound 40:2-(1-Ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

40.A. Synthesis of (5-Fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.C. except using 5-fluoro-1H-indoleas the indole component afforded the title compound as a solid.

40.B. Synthesis of(1-Ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(5-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil.

40.C. Synthesis of2-(1-Ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the carboxylic acid component afforded the titlecompound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.91 (br, 1H), 7.22 (dd,1H), 7.14 (dd, 1H), 6.90 (ddd, 1H), 4.05 (m, 1H), 4.00 (m, 1H), 3.68 (m,2H), 2.71 (dt, 1H), 2.69 (br, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.97 (m,1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH⁺), ESI (−) MSm/e=262 (MH⁻).

Compound 41:2-(6-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

41.A. Synthesis of (5-Chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.C. except using 5-chloro-1H-indoleas the indole component afforded the title compound as a solid. ¹H NMR(500 MHz, DMSO-d₆) δ 12.54 (br, 1H), 8.50 (d, 1H), 8.12 (d, 1H), 7.56(d, 1H), 7.30 (dd, 1H), 4.36 (q, 2H), 2.48 (t, br, 1H), 1.32 (t, 3H);APCI (−) MS m/e=250 (MH⁻).

41.B. Synthesis of(6-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(5-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil. ¹H NMR (500 MHz, CDCl₃)δ 9.18 (br, 1H), 7.46 (d, 1H), 7.26 (d, 1H), 7.11 (dd, 1H), 4.19 (m,2H), 4.03 (m, 1H), 3.93 (m, 1H), 2.99 (d, 1H), 2.90 (d, 1H), 2.77 (m,1H), 2.72 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.27 (t, 3H), 0.81 (t,3H); APCI (+) MS m/e=322 (MH⁺), APCI (−) MS m/e=320 (MH⁻).

41.C Synthesis of(6-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.50 (br, 1H), 8.68 (br, 1H), 7.46 (s,1H), 7.23 (d, 1H), 7.12 (d, 1H), 4.09 (m, 1H), 4.03 (m, 1H), 3.03 (d,1H), 2.99 (d, 1H), 2.79 (m, 2H), 2.10 (m, 1H), 2.01 (m, 1H), 0.86 (t,3H); ESI (+) MS m/e=294 (MH⁺), ESI (−) MS m/e=292 (MH⁻).

41.D. Synthesis of2-(6-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (br, 1H), 7.46 (s, 1H), 7.22 (d,1H), 7.12 (d, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.67 (m, 2H), 2.83 (m,1H), 2.72 (m, 1H), 2.65 (br, 1H), 2.19 (m, 1H), 2.00 (m, 2H), 1.88 (m,1H), 0.92 (t, 3H); APCI (+) MS m/e=280 (MH⁺), APCI (−) MS m/e=278 (MH⁻).

Compound 42:2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

42.A. Synthesis of (5-Bromo-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36, step (c) except using5-bromo-1H-indole as the indole component afforded the title compound asa solid.

42.B. Synthesis of(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidethyl ester

Following the procedure of example 36.B. except using(5-bromo-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil.

42.C. Synthesis of2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 28.C. except using(6-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acidethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (br, 1H), 7.62 (d, 1H), 7.24 (dd,1H), 7.19 (d, 1H), 4.05 (m, 1H), 3.97 (m, 1H), 3.67 (m, 2H), 2.84 (m,1H), 2.71 (m, 1H), 2.55 (br, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 1.97 (m,1H), 1.88 (m, 1H), 0.91 (t, 3H); ESI (+) MS m/e=324 (MH⁺), ESI (−) MSm/e=322 (MH⁻).

Compound 43:2-(1-Ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

43.A. Synthesis of (6-Fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.C. except using 6-fluoro-1H-indoleas the indole component afforded the title compound as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.75 (br, 1H), 8.48 (d, 1H), 8.39 (dd, 1H), 7.12 (m,2H), 4.41 (q, 2H), 1.43 (t, 3H); ESI (−) MS m/e=234 (MH⁻).

43.B. Synthesis of(1-Ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(6-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil.

43.C. Synthesis of(1-Ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 11.8 (br, 1H), 9.53 (br, 1H), 7.29 (dd,1H), 6.93 (dd, 1H), 6.74 (ddd, 1H), 3.94 (m, 1H), 3.89 (m, 1H), 2.86 (d,1H), 2.82 (d, 1H), 2.69 (m, 1H), 2.66 (m, 1H), 2.03 (m, 1H), 1.95 (m,1H), 0.74 (t, 3H); ESI (+) MS m/e=278 (MH⁺), ESI (−) MS m/e=276 (MH⁻).

43.D. Synthesis of2-(1-Ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (br, 1H), 7.40 (dd, 1H), 7.00 (dd,1H), 6.88 (ddd, 1H), 4.06 (m, 1H), 3.99 (m, 1H), 3.65 (m, 2H), 2.85 (m,1H), 2.71 (m, br, 2H), 2.18 (m, 1H), 2.02 (m, 1H), 1.98 (m, 1H), 1.88(m, 1H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH⁺), ESI (−) MS m/e=262(MH⁻).

Compound 44:2-(7-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

44.A. Synthesis of (6-Chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester

Following the procedure of example 36.c. except using 6-chloro-1H-indoleas the indole component afforded the title compound as a solid. ¹H NMR(500 MHz, CDCl₃) δ 11.50 (br, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 7.37 (d,1H), 7.15 (dd, 1H), 4.31 (q, 2H), 1.33 (t, 3H); ESI (+) MS m/e=252(MH⁺), ESI (−) MS m/e=250 (MH⁻).

44.B. Synthesis of(7-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 22.D. except using(6-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as an oil.

44.C. Synthesis of(7-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 11.80 (br, 1H), 9.57 (br, 1H), 7.30 (d,1H), 7.24 (d, 1H), 6.95 (dd, 1H), 3.97 (m, 1H), 3.88 (m, 1H), 2.88 (d,1H), 2.80 (d, 1H), 2.71 (m, 1H), 2.66 (dt, 1H), 2.04 (m, 1H), 1.96 (m,1H), 0.74 (t, 3H); ESI (+) MS m/e=294 (MH⁺), ESI (−) MS m/e=292 (MH⁻).

44.D. Synthesis of2-(7-Chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (br, 1H), 7.40 (d, 1H), 7.30 (d,1H), 7.08 (dd, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.66 (m, 2H), 2.73 (dt,1H), 2.71 (br, 1H), 2.11 (m, 1H), 2.02 (m, 1H), 1.96 (m, 1H), 1.88 (m,1H), 0.91 (t, 3H); ESI (+) MS m/e=280 (MH⁺), ESI (−) MS m/e=278 (MH⁻).

Compound 45:2-(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

45.A. Synthesis of 5,7-Dimethyl-1H-indole

To solution of 5,7-dimethyl-1H-indole-2,3-dione in tetrahydrofuran at 0°C. was added 1.0 M solution of borane-tetrahydrofuran complex intetrahydrofuran (40 mL). After stirred at room temperature overnight, a5% HCl solution was added to the mixture and it was stirred 20 minutes.It was neutralized with saturated sodium bicarbonate solution andextracted with ethyl acetate. Extracts were dried over magnesium sulfateand evaporated to dryness to afford the title compound as oil.

45.B. Synthesis of (5,7-Dimethyl-1H-indol-3-yl)-oxo-acetic acid ethylester

Following the procedure of example 36.C. except using5,7-dimethyl-1H-indole as the indole component afforded the titlecompound as a solid. ESI (+) MS m/e=246 (MH⁺).

45.C. Synthesis of(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(5,7-dimethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester componentafforded the title compound as an oil.

45.D. Synthesis of(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.50 (br, 1H), 8.28 (br, 1H), 7.14 (s,1H), 6.82 (s, 1H), 4.10 (m, 1H), 4.06 (m, 1H), 3.02 (d, 2H), 3.01 (d,1H), 2.81 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.10 (m, 1H), 2.03 (m,1H), 0.87 (t, 3H); ESI (+) MS m/e=288 (MH⁺), ESI (−) MS m/e=286 (MH⁻).

45.E. Synthesis of2-(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.51 (br, 1H), 7.15 (s, 1H), 6.83 (s,1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.67 (m, 2H), 2.85 (m, 1H), 2.72 (dt,1H), 2.69 (br, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H), 2.06 (m,1H), 2.03 (m, 1H), 1.89 (m, 1H), 0.95 (t, 3H); ESI (+) MS m/e=274 (MH⁺),ESI (−) MS m/e=272 (MH⁻).

Compound 46:2-(6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

46.A. Synthesis of 5,7-Dichloro-1H-indole

Following the procedure of example 45.A. except using5,7-dichloro-1H-indole-2,3-dione as the dione component afforded thetitle compound as a oil.

46.B. Synthesis of (5,7-Dichloro-1H-indol-3-yl)-oxo-acetic acid ethylester

Following the procedure of example 36.C. except using5,7-dichloro-1H-indole as the indole component afforded the titlecompound as a solid.

46.C. Synthesis of(6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(5,7-dichloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester componentafforded the title compound as an oil.

46.D. Synthesis of(6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 22.B. except using(6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (br, 1H), 7.03 (d, 1H), 6.97 (d,1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.15 (t, 2H), 3.10 (d, 1H), 3.03 (d,1H), 2.15 (m, 1H), 2.05 (m, 1H), 0.88 (t, 3H); ESI (+) MS m/e=328 (MH⁺),ESI (−) MS m/e=326 (MH⁻).

46.E. Synthesis of2-(6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 22.C. except using(6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (br, 1H), 7.03 (d, 1H), 6.98 (d,1H), 4.03 (m, 1H), 3.99 (m, 1H), 3.71 (m, 2H), 3.13 (m, 2H), 2.57 (br,1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.04 (m, 1H), 1.92 (m, 1H), 0.93 (t,3H); ESI (+) MS m/e=314 (MH⁺), ESI (−) MS m/e=312 (MH⁻).

Compound 47:2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

47.A. Synthesis of N-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide

Following the procedure of example 36.A. except using4-bromo-2-ethylaniline as the aniline component afforded the titlecompound as a solid. ESI (−) MS m/e=269 (MH⁻).

47.B. Synthesis of 5-Bromo-7-ethyl-1H-indole-2,3-dione

Following the procedure of example 36.B. except usingN-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide as the acetamidecomponent afforded the title compound as a solid. ESI (−) MS m/e=252(MH⁻).

47.C. Synthesis of (5-Bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethylester

Following the procedure of example 36.C. except using5-Bromo-7-ethyl-1H-indole-2,3-dione as the dione component afforded thetitle compound as a solid. ESI (+) MS m/e=324 (MH⁺), ESI (−) MS m/e=322(MH⁻).

47.D. Synthesis of(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester

Following the procedure of example 36.D. except using(5-bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the estercomponent afforded the title compound as a solid.

47.E. Synthesis of2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 28.C. except using(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid ethyl ester as the ester component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (br, 1H), 7.48 (d, 1H), 7.11 (d,1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.70 (m, 2H), 2.80 (m, 3H), 2.71 (dt,1H), 2.55 (br, t, 1H), 2.19 (m, 1H), 2.05 (m, 1H), 2.01 (m, 1H), 1.90(m, 1H), 1.33 (t, 3H), 0.92 (t, 3H); ESI (+) MS m/e=352 (MH⁺), ESI (−)MS m/e=350 (MH⁻).

Compound 48:2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-N,N-dimethyl-acetamide

2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-N,N-dimethyl-acetamide

Following the procedure of example 27 except using dimethylamine as theamine component afforded the title compound as a solid. ¹H NMR (500 MHz,CDCl₃) δ 9.39 (br, 1H), 7.35 (d, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.19(m, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 2.84 (s, m, 9H), 2.11 (m, 1H), 2.01(m, 1H), 1.36 (t, 3H), 0.85 (t, 3H); ESI (−) MS m/e=299 (MH⁻).

Compound 49:2-(9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Compound 49 was synthesized according to the following scheme:

49.A. Synthesis of(9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

To a solution of(1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid(0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was addedsodium hydride (60% dispersion in mineral oil, 0.4 g). After beingheated at 50° C. for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was addedand the solution was stirred for another 2 hours. It was quenched withethyl acetate and washed with water. The ethyl acetate layer was driedover magnesium sulfate and evaporated to dryness. Flash chromatographyon silica gel provided 0.486 g (73%) of the title compound as a solid.¹H NMR (500 MHz, CDCl₃) δ 7.13 (m, 3H), 6.97 (d, 1H), 6.74 (d, 1H), 6.68(t, 1H), 6.21 (d, 1H), 3.90 (s, 1H), 3.63 (m, 1H), 3.35 (td, 1H), 3.18(d, 1H), 3.00 (d, 1H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1H), 1.85(d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+)MS m/e=278 (MH⁺).

49.B. Synthesis of2-(9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

To a solution of(9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran andit was stirred at 90° C. for 4 hours. The mixture was quenched with 5%HCl solution and stirred at room temperature for 20 minutes. It wasextracted with ethyl acetate and washed with saturated sodiumbicarbonate. The extracts were dried over magnesium sulfate andevaporated to dryness. Flash chromatography on silica gel provided 0.321g (74%) of the title compound as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.17(m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1H), 6.56 (d, 1H), 3.87(m, 1H), 3.79 (m, 1H), 3.68 (dt, 1H), 3.64 (br, 1H), 3.41 (td, 1H), 2.93(q, 2H), 2.43 (q, 2H), 2.04 (m, 1H), 1.93 (dt, 1H), 1.86 (m, 1H), 1.77(m, 1H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H).

Compound 50:2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

50.A. Synthesis of2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid

Following the procedure of example 49.A. except using(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid asthe indole component afforded the title compound as an oil.

50.B. Synthesis of2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol

Following the procedure of example 49.B. except using2-(1,8-diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-aceticacid as the carboxylic acid component afforded the title compound as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.35 (dd, 1H), 7.03 (t, 1H), 6.98 (d,1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.91 (s, 3H), 3.75 (m, 1H), 3.63 (m,1H), 3.11 (q, 2H), 2.87 (m, 1H), 2.76 (dt, 1H), 2.68 (br, 1H), 2.27 (m,1H), 2.22 (m, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.35 (t, 3H), 0.94 (t,3H); ESI (+) MS m/e=288 (MH⁺).

Compound 51:2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)ethanol

51.A. Synthesis of Ethyl2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate

(R,S)-Etodolac ethyl ester (5 g, 15.8 mmol) was dissolved in chloroform(50 ml) and cooled to −60° C. with a dry ice/acetone bath. To thissolution was added dropwise a solution of bromine (2.53 g, 15.8 mmol) inchloroform (50 ml) during 2 hr. After the addition, the reaction mixturewas allowed to warm to −20° C. and triethylamine (5 ml) was addeddropwise followed by silica gel (˜20 g). The mixture was stirred for 10min, filtered through silica gel (˜10 g), and the filtrate evaporated todryness. The crude product was recrystallized in hexane/dichloromethane(60 ml/20 ml) to give (4.5 g, 72%) of product. ¹H NMR (300 MHz, CDCl₃) δ9.23 (b, NH), 7.45 (d, 1H), 7.15 (d, 1H), 4.21 (qrt, 2H), 4.15 (m, 1H),3.95 (m, 1H), 3.25 (dd, 2H), 2.94 (m, 2H), 2.25 (m, 1H), 2.1 (m, 1H),1.45 (t, 3H), 1.15 (t, 3H), 0.85 (t, 3H).

51.B. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)aceticacid

To a stirred solution of ethyl2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate(2.8 g, 5 mmol) in dioxane (40 ml) was added lithium hydroxidemonohydrate (2.8 g, 67 mmol) and water (30 ml). The mixture was stirredat room temperature overnight. It was concentrated under reducedpressure, neutralized with 5% HCl, extracted with CH₂Cl₂, dried overMgSO₄, and concentrated. The crude product was recrystallized indichloromethane/hexane (60 ml/20 ml) to give a white solid (980 mg,53%). ¹H NMR (300 MHz, CDCl₃) δ 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d,1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H), 2.80 (m, 2H), 2.09(m, 2H), 1.24 (t, 3H), 0.874 (t, 3H).

51.C. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)ethanol

To a stirred solution of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)aceticacid (0.87 g, 2.4 mmol) in THF (5 ml), was added dropwise via syringeborane-tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6ml, 3.6 mmol) during 30 min. The mixture was stirred at 90° C. for 8 hr,cooled, quenched with distilled water and 5% HCl, extracted with EtOAc.The organic phases collected, washed with brine, dried over MgSO₄, andevaporated to give a residue which was chromatographed on silica gel.Elution with hexane-EtOAc (1:1) gave the product which was furtherrecrystallized in hexane/dichloromethane to give the product (0.64 g,76%). ¹H NMR (300 MHz, CDCl₃) δ 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d,1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1H), 2.81 (m, 1H), 2.75 (t,1H), 2.69 (t, 1H), 2.58 (t, 1H), 2.19 (m, 1H), 2.04 (m, 2H), 1.26 (t,3H), 0.93 (t, 3H).

Compound 54:2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol

54.A. Synthesis of 2-(Hydroxyimino)-N-(2-isopropylphenyl)acetamide.

In a 2-1 round-bottomed flask are placed water (1000 ml), followed bychloral hydrate (49 g, 0.30 mol), anhydrous sodium sulfate (225 g),2-isopropylaniline (50 g, 0.37 mol), concentrated hydrochloric acid (22ml, 0.26 mol), hydroxylamine hydrochloride (57 g, 0.81 mol). Thesolution was boiled for 3 hr, cooled, quenched with water, and extractedwith ethyl acetate. The extracts were dried over MgSO₄, and evaporated.The residue was purified by elution from a silica gel column withhexane/EtOAc (7:3) to afford the product (26.7 g, 35%). ¹H NMR (300 MHz,CDCl₃) δ 8.28 (br, NH), 7.88 (dd, 1H), 7.82 (b, NOH), 7.63 (s, N═CH),7.24 (m, 3H), 3.04 (m, 1H), 1.27 (d, 6H); ESI (+) MS m/e=207 (MH⁺), ESI(−) MS m/e=205 (MH⁻).

54.B. Synthesis of 7-Isopropylindoline-2,3-dione

To a stirred solution of concentrated H₂SO₄ (210 ml) and H2O (50 ml),was added over 20 min (26.7 g, 0.13 mol) of2-(hydroxyimino)-N-(2-isopropylphenyl)acetamide. The mixture was stirredat 75° C. for 2 hr, cooled and poured onto cracked ice. After standingfor 15 min, it was extracted with EtOAc, washed with water, dried overMgSO₄, and concentrated. Air drying afforded (23.8 g, 97%) of crudeproduct). ¹H NMR (300 MHz, CDCl₃) δ 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t,1H), 2.87 (m, 1H), 1.30 (d, 6H); ESI (+) MS m/e=190 (MH⁺), ESI (−) MSm/e=188 (MH⁻).

54.C. Synthesis of 5-Bromo-7-isopropylindoline-2,3-dione

7-isopropylindoline-2,3-dione (23.8 g, 0.12 mol) was added to a stirredsolution of glacial acetic acid (700 ml). To this solution was added,via additional funnel bromine (7.8 ml, 0.15 mol) in glacial acetic acid(300 ml) during 30 min. After the addition, the combined mixture wasstirred at 75° C. for 3 hr, cooled, and extracted with EtOAc. Theorganic extracts were washed with brine, dried over MgSO₄, andevaporated in vacuo; air dried to give (31.8 g, 94%) of crude product.¹H NMR (300 MHz, CDCl₃) δ 8.04 (b, NH), 7.59 (dd 2H), 2.84 (m, 1H), 1.31(d, 6H); ESI (+) MS m/e=269 (MH⁺), ESI (−) MS m/e=267 (MH⁻).

54.D. Synthesis of 5-Bromo-7-isopropyl-1H-indole

To a stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g,0.17 mol) in THF (275 ml) at room temperature under a nitrogenatmosphere, was added, via syringe, 2.0 M solution of LiBH₄/THF (215 ml)over 30 min. The reaction mixture was stirred at 90° C. for 1 hr,cooled, quenched with distilled water and 5% HCl, and extracted withEtOAc. The extracts were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The crude product was purified byelution from a silica gel column with hexane/EtOAc (9:1) to give (14.5g, 36%) of the product. ¹H NMR (300 MHz, CDCl₃) δ 8.18 (b, NH), 7.62 (d,1H), 7.21 (t, 1H), 7.16 (d, 1H), 6.51 (dd, 1H), 3.20 (m, 1H), 1.38 (d,6H); ESI (+) MS m/e=239 (MH⁺), ESI (−) MS m/e=237 (MH⁻).

54.E. Synthesis of Ethyl2-(5-Bromo-7-isopropyl-1H-indol-3-yl)-2-oxoacetate

A 2.0 M solution of oxalyl dichloride in dichloromethane (60 ml, 0.12mol) was added dropwise during 10 min to a solution of5-Bromo-7-isopropyl-1H-indole (14.5 g, 0.061 mol) in Et₂O (220 ml) atroom temperature under a nitrogen atmosphere. The mixture was stirredfor 4.5 hr. The Et₂O was removed by evaporation and absolute EtOH (220ml) was added. The resulting mixture was stirred at room temperatureunder a nitrogen atmosphere overnight. The EtOH was evaporated, andEtOAc was added to the residue and washed with sat. NaHCO₃ and brine.The organic layers were dried over MgSO₄, concentrated, and dried undervacuume to give a crude product (13.8 g, 67%). ¹H NMR (300 MHz, CDCl₃) δ8.85 (b, NH), 8.46 (dd, 2H), 7.33 (d, 1H), 4.42 (qrt, 2H), 3.21 (m, 1H),1.44 (t, 3H), 1.38 (d, 6H), ESI (+) MS m/e=339 (MH⁺), ESI (−) MS m/e=337(MH⁻).

54.F. Synthesis of 2-(5-Bromo-7-isopropyl-1H-indol-3-yl)ethanol. Ethyl2-(5-bromo-7-isopropyl-1H-indol-3-yl)₇₋₂-oxoacetate (13.8 g, 0.04 mol)in THF (300 ml) was reduced with 2.0 M solution of LiBH₄ in THF (50 ml,0.1 mol) by refluxing under nitrogen atmosphere for 5 hr, cooled,quenched with distilled water and 5% HCl, and extracted with EtOAc. Theextracts were washed with brine, dried over MgSO₄, and concentrated. Thecrude product was purified by eluting from silica gel with hexane/EtOActo obtain (4.5 g, 39%) of product. ¹H NMR (300 MHz, CDCl₃) δ 8.05 (b,NH), 7.59 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.89 (t, 2H), 3.18 (m,1H), 2.98 (t, 2H), 1.37 (d, 6H); ESI (+) MS m/e=283 (MH⁺), ESI (−) MSm/e=281 (MH⁻).

54.G. Synthesis of Ethyl2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate

To a suspension of 2-(5-bromo-7-isopropyl-1H-indol-3-yl)ethanol (4.5 g,0.016 mol) under nitrogen atmosphere was added boron trifluoride diethyletherate (2.2 ml, 0.18 mol), followed by dropwise addition of ethylpropionyl acetate (3.4 ml, 0.024 mol) over ten minutes. The mixture wasstirred at room temperature for 1.5 hr. Dichloromethane was added to themixture and the organic layer washed with sat. NaHCO₃ and water, anddried over MgSO₄. The solvent was concentrated and air dried to give acrude product (6 g, 92%). ESI (+) MS m/e=409 (MH⁺), ESI (−) MS m/e=407(MH⁻).

54.F. Synthesis of2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol

To a stirred solution of ethyl2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate(6.0 g, 0.015 mol) in THF (120 ml), was added 2.0 M solution ofLiBH₄/THF (20 ml, 0.30 mol) via syringe during 30 min under a nitrogenatmosphere at room temperature. The mixture was refluxed for 10 hr,cooled, quenched with water and 5% HCl, and extracted with EtOAc. Theorganic phases were combined and washed with brine, dried over MgSO₄,and evaporated to give a residue, which was chromatographed on silicagel. Elution with hexane-EtOAc (7:3) gave the product (4.3 g, 80%). ¹HNMR (300 MHz, CDCl₃) δ 8.18 (b, NH), 0.92 (t, 3H), 1.35 (d, 6H), 1.98(m, 3H), 2.19 (m, 1H), 2.54 (t, 1H), 2.75 (m, 2H), 3.17 (m, 1H), 3.71(t, 1H), 4.03 (m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI(+) MS m/e=367 (MH⁺), ESI (−) MS m/e=365 (MH⁻).

Compound 55: ethyl3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate

55.A. Synthesis of (E)-ethyl3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)acrylate

A suspension of Pd(OAc)₂ (0.2 g, 0.8 mmol), P(o-tolyl)₃ (0.25 g, 0.8mmol),2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol(1.5 g, 4.1 mmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate(1.8 ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogenatmosphere at 100° C. for 24 hr. The mixture was allowed to cool,quenched with water, worked-up with dichloromethane, and washed withbrine. The organic layers were dried over MgSO₄ and concentrated underreduced pressure. The crude product was chromatographed on silicahexane/EtOAc (6:4) to give the product (0.9 g, 56%). %). ¹H NMR (300MHz, CDCl₃) δ 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H),6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1H),2.84 (m, 1H), 2.77 (d, 1H), 2.52 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H),1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MSm/e=386 (MH⁺), ESI (−) MS m/e=384 (MH⁻).

55.B. Synthesis of Ethyl3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate

To a suspension of (E)-ethyl3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)acrylate(0.8 g, 2.3 mmol) in 2% HCl in EtOH (80 ml) was added palladium oncarbon (10%, 0.5 g). The mixture was stirred under an atmosphere ofhydrogen (1 am) at room temperature for 24 hr. The catalyst filteredthrough celite. The filtrate was evaporated at reduced pressure. Theresidue was neutralized with sat. NaHCO₃, extracted with EtOAc, anddried over MgSO₄. The solvent was concentrated under reduced pressureand purified by silica gel flash column chromatography hexane/EtOAc(6:4) to give the product (0.33 g, 38%). ¹H NMR (300 MHz, CDCl₃) δ 7.72(br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70(m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m, 3H), 2.18(m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94(t, 3H); ESI (+) MS m/e=388 (MH⁺), ESI (−) MS m/e=386 (MH⁻).

Compound 56:3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoicacid

56.A. Synthesis of3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoicAcid

To a stirred solution of ethyl3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate(0.28 g, 0.72 mmol) in dioxane (6 ml) was added lithium hydroxidemonohydrate (0.18 g, 4.3 mmol) and water (3 ml). The mixture was stirredat room temperature for 8 hr. It was concentrated under reducedpressure, neutralized with 5% HCl, extracted with EtOAc, and dried overMgSO₄. The solvent concentrated and purified by silica gel flash columnchromatography dichloromethane/methanol (8:2) to give the product (0.09g, 35%). ¹H NMR (300 MHz, CDCl₃) 6.7.77 (br, NH)), 7.19 (d, 1H), 6.91(d, 1H), 4.04 (m, 2H), 3.68 (m, 2H), 3.16 (m, 1H), 3.06 (t, 2H), 2.85(m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94(t, 3H); ESI (+) MS m/e=360 (MH⁺), ESI (−) MS m/e=358 (MH⁻).

Compound 57:3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propan-1-ol

57.A. Synthesis of3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propan-1-ol

A solution of ethyl3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate(0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 ml) was stirred atroom temperature under a nitrogen atmosphere. LiAlH₄ (0.09 g, 2.4 mmol)was slowly added to the solution. The mixture was stirred for 18 hr,quenched with water and 5% HCl, extracted with EtOAc, dried over MgSO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel flash column chromatography hexane/EtOAc (4:6) twice togive (31 mg) of the product (0.031 g, 20%). ¹H NMR (300 MHz, CDCl₃) δ7.70 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.03 (m, 2H), 3.73 (m, 4H),3.17 (m, 1H), 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H),1.26 (br, 1H), 0.94 (t, 3H); ESI (+) MS m/e=346 (MH⁺), ESI (−) MSm/e=344 (MH⁻).

Example 2 Biological Data

Cox-1

Test compound and/or vehicle is incubated with human platelets (10⁸/ml)containing the phospholipase inhibitor MLnFP (100 μM) for 15 minutes at37° C. Arachidonic acid (100 μM) is then added for a further 15 minuteincubation period. The reaction is stopped by addition of 1 N HCl andneutralized with 1N NaOH. PGE₂ levels in the supernatant are determinedusing the Amersham EIA kit. Compounds are screened at 10 μM. Cox assaysare described in Chan et al. 1999 J Pharmacol Exp Ther. 290:551-560; andSwinney et al. 1997, J Biol Chem. 272:12393-12398; both incorporatedherein by reference.

Cox-2

Cyclooxygenase-2 (human recombinant, expressed in Sf9 cell, Cayman60122) is used. Test compound and/or vehicle is pre-incubated with 0.11U cyclooxygenase-2, 1 mM reduced glutathione (GSH), 500 μM phenol and 1μM hematin for 15 minutes at 37° C. The reaction is initiated byaddition of 0.3 μM arachidonic acid as substrate in Tris-HCl pH 7.7 andterminated after a 5 minute incubation at 37° C. by addition of 1N HCl.Following centrifugation, substrate conversion to PGE₂ is measured by anAmersham EIA kit. Compounds are screened at 10 μM. COX-2 assays aredescribed in Riendeau, D., et al., 1997 Can. J. Physiol. Pharmacol.75:1088-1095; and Warner, J. D., et al., 1999 Proc. Natl. Acad. Sci.U.S.A. 96: 7563-7568; both incorporated herein by reference.

Provided below in Table I are exemplary results for COX-1 and COX-2inhibition by compounds described herein: TABLE I Compound COX-1 COX-1COX-2 COX-2 No. (IC50 μM) % Inhibition (IC50 μM) % InhibitionEtodolac >300 −25 >300 −14 1 <10 96 <10 100 7 94 99 9 88 90 27 >30024 >300 3 35 >300 −69 >300 −10 36 >300 −4 >300 18 47 68.6 45 >100 78 5278 97 53 90 96Inhibition of β-Catenin

Inhibition of β-catenin was measured using a reporter assay based on theassay described in Korinek et al. 1997 Science 275:1784-1787 andemploying the reporter plasmid TOPFLASH.

On Day 1, HEK-293 cells (ATCC) were plated in 24-well plates (VWR) at40,000 cells per well in 450 μL DMEM+10×FBS media and incubatedovernight at 37° C., 5% CO₂.

On Day 2, TOPFLASH plasmid (Upstate Cell Signaling Solutions, VA), pGL3control vector (Promega), and a plasmid encoding for constitutivelyexpressed human β-catenin (Hans Clevers) were separately diluted to 0.1μg/μL in TE Buffer. Transfections were done using FuGene 6 TransfectionReagent (Roche). Transfection mixtures included either 8 μl of 0.1 μg/μlpGL3 in 400 μl serum free media (DMEM, Gibco) and 9.6 μl FuGene, or 8 μlof 0.1 μg/μl TOPFLASH and 16 μl of 0.1 β-catenin plasmid in 400 μl serumfree media (DMEM, Gibco) and 9.6 μl FuGene. The transfection mixtureswere gently mixed and incubated for 15-30 min at room temperature. Fiftyμl of the appropriate transfection mixture was added dropwise to the 293cells and the cells incubated overnight at 37° C., 5% CO₂.

On Day 3, the compounds to be tested were diluted to 0.25M indimethylsulfoxide (DMSO). This solution was then used to make a 3×dilution of compound into DMEM+10% FBS, e.g., 100 μm to 300 μm.Two-hundred and fifty μl of the 3× diluted compound was added drop-wiseto an appropriate well containing 50011 of media. This was swirledgently. After mixing, 25011 of the diluted 3× compound was added toanother well and the procedure followed until the compound was diluteddown three times. Plates were incubated for 24 hrs at 37° C., 5% CO₂.Experiments were performed in duplicate.

On Day 4, Luciferase activity was measured using a Promega Steady-Glo®luciferase assay system (Promega Cat. No. EC251) according to themanufactures instructions. The cells and Glo Lysis buffer wereequilibrated to room temperature. Ten mls of Glo Lysis® Buffer was addedto reconstitute the Steady-Glo® Assay Reagent. Five hundred μl of theGlo Lysis Buffer®/Assay Reagent were added to each well. The reactionwas incubated for 5 min on a shaker at room temperature. 100 μl oflysate was transferred to a white 96-well plate and read on a Tecan(Research Triangle Park, N.C.) GENios microplate reader, using theluminescence setting.

Inhibition of β-catenin:TOP flash by some compounds of the invention isshown in FIG. 1.

Cell Cytotoxicity

Normal prostate cells (PREC, Cambrex East Rutherford N.J.), prostatecancer cell line (LNCaP, ATCC), PBL (peripheral blood leukocytes-buffycoat San Diego Blood Bank), and primary CLL cells were incubated for oneto two days in RPMI-1640 and 10% FBS (fetal bovine serum). They wereplated in 96-well plates at 100,000 cells/well. Titrated concentrationsof the compound to be tested were added to the culture medium. The cellswere incubated three days at 37° C., 5% CO₂. Viability of the cells wasassayed by standard MTT assay. Each drug concentration was done induplicate. MTT assay: 10 μl of 12 mM3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)(SIGMA) was added to each well. The cells were incubated at 37° C., 5%CO₂ for 4 hours. 100 μl of 20% SDS, 0.015M HCl was added to each welland the cells were incubated overnight. The plates were read atabsorbance 595 nM.

Cytotoxicty results are shown in Table II and Table III. TABLE IICompound LNCap PREC IC50 No. IC50 (nm) (nm) Etodolac 122 416 1 14 53 712 9 10 22 163 23 70 24 80 25 60 26 95 27 52 140 28 25 29 80 30 100 3137 32 15 33 132 34 20 35 68 220 36 30 160 37 60 38 23 39 46 40 80 41 5142 12 43 77 44 60 45 8 46 18 47 3 14 48 60 51 10 52 9 53 11 54 7 55 1856 235 57 110

TABLE III Compound CLL PBL No. IC50 (nm) IC50 (nm) Etodolac 200 350 1 7276 27 52 150 31 244 32 250 33 98 36 50 160 38 73 35 100 140 39 120 40185 41 110 45 90 46 20 47 21 60 48 240

Selected analogs were tested and compared in several tumor cell linesand their multidrug-resistant (MDR) sublines. The MDR cell lines used inthese experiments have been extensively characterized in the literatureand are resistant to several widely used anti-cancer drug, such asdoxorubicin, paclitaxel, etoposide, and others. As shown in Table IV,Table V and Table VI, the selected analogs were found to be about10-20-fold more potent when compared to Etodolac. In addition, noappreciable loss of activity was observed in the multidrug resistantsub-lines, when compared to the parental cells. TABLE IV Ovarian OvarianBreast Breast Leukemia Leukemia Compound MES-SA MES-SA/Dx5 MCF-7 MCF-7HL-60 HL-60/ADR No. (parental) (resistant) (parental) (parental)(parental) resistant Etodolac 700 430 625 >1000 300 550 1 26 18 14 21 1316 36 100 63 54 80 38 50 47 24 15 19 20 13 23

TABLE V Kidney Colon Colon Compound HEK- Lung Colon HCT HT- ProstateProstate Prostate No. 293 A549 SW480 116 29 DU145 PC3 LNCap Etodolac 900800 355 195 750 266 240 93 1 23 10 23 17 30 48 40 11 36 NT NT NT NT 105NT NT NT 47 47 26 16 8 25 <20 <20 <20

TABLE VI Compound No. RMPI8226 micromolar Etodolac 140 36 75 47 16 54 2055 37 56 238 57 320

Antiangiogenic Assay

To determine the effects of COX inhibitors on angiogenesis in vivo,selective compounds will be tested in the mouse and rat cornealmicropocket assay. The mouse corneal neovascularization micropocketmodel is performed with materials, reagents and procedures essentiallyas described by Muthukkauppah et al., 1982 J. Natl. Cancer Inst., 69,699-708. In this assay, a pellet containing basic fibroblast growthfactor (FGF) is implanted into the corneal stroma of the mouse and thenewly formed vessels are measured using a slit lamp. In this model,COX-2 is expressed in the endothelial cells of the newly developed bloodvessels. The ability of a compound of the invention to inhibitFGF-induced angiogenesis in the mouse will be tested using the abovemethod. The inhibitory effects of the compounds of the invention in themouse cornea model will be tested using another angiogenic stimulus,vascular endotherlial growth factor (VEGF).

Cyclin D1

Cyclin D1 Transcript Expression Levels as measured by quantitative PCRassay. LNCaP cells were cultured at 37° C., 5% CO₂ for 24 hoursuntreated or in the presence of R-etodolac (200 μM), compound 42 (50μM), compound 36 (100 μM), or compound 1 (20 μM) (see Table II forstructures). Cells were harvested by trypsinization, washed with PBS,and stored at −80° C. Total cellular RNA was prepared from cell pelletsusing the RNEasy® Mini kit (Qiagen, Inc., Valencia, Calif.). RNA wasquantified by spectrophotometer. Approximately 2 μg of RNA was used toprepare cDNA using the ThermoScript™ RT-PCR System (Invitrogen,Carlsbad, Calif.).

The levels of cyclin D1 transcripts in the cDNA samples were measuredusing a quantitative PCR (qPCR) assay specific for cyclin D1. The cyclinD1 transcript was amplified using the following primer pair: Cyclin D15′-AATGACCCCGACCGATT-3′ (SEQ ID NO:1) for: Cyclin D15′-GCACAAGAGGCAACGAAG G-3′ (SEQ ID NO:2) rev:

The cyclin D1 primers are described in a manuscript from Takayasu et al.(2001 Clin. Cancer Res. 7:901-908). All assays were performed induplicate. All qPCR assays were performed and analyzed using a Bio-RadiCycler (Bio-Rad, Hercules, Calif.). The levels of cyclin D1 transcriptswere normalized for total input cDNA by performing a separate assay todetect the levels of a housekeeping gene (18s) using the followingprimer pair: 18s for: 5′-CGCCGCTAGAGGTGAAATTC-3′ (SEQ ID NO:3) 18s rev:5′-TTGGCAAATGCTTTCGCTC-3′ (SEQ ID NO:4)

The samples were normalized for 18s transcript levels using the methodof Livak et al. (2001 Methods 25:402-408). The level of cyclin D1transcripts in the control sample was set to 1. FIG. 2 represents theaveraged normalized cyclin D1 transcripts±standard deviation for threeindependent experiments (two independent experiments for compound 1).The data show that compound 42, compound 36, and compound 1 inhibitcyclin D1 mRNA expression.

Western blot analysis of LNCaP cell lysates from cells treated withR-etodolac, compound 42, compound 36, or compound 1 using a monoclonalantibody specific for Cyclin D1 (BD Pharmingen) confirmed that thecompounds reduced Cyclin D1 protein expression.

Other Cyclin D proteins have been shown to be dependent on theWnt/beta-catenin pathway (e.g., cyclin D2—Briata et al. 2003 Mol. Cell12:1201-11) and would be expected to be affected by the compounds of theinvention in a similar way as Cyclin D1. The inhibition of cyclin Dexpression by the compounds of the invention can also be used as abiomarker of the efficacy of these compounds.

Example 3 Daudi Lymphoma Murine Xenograft Model Mice Studies

Materials

Male SCID mice, 6-8 weeks of age, obtained from Simonsen Laboratories,Inc. (Gilroy, Calif.) were housed in groups of five.

The Daudi human Burkitt Lymphoma cells were obtained from American TypeCulture Collection and were inoculated subcutaneously (1.0×107cells/mouse) on the flanks of SCID mice. After the tumors reachedapproximately 100 mm³ treatment was initiated.

Body weights and tumor volume of all mice were measured and recordedtwice weekly. Tumors were measured in three dimensions and volumecalculated using the formula: 4 3πr3. Time for the tumors (days) to growto 4× and 8× the initial volume at dosing were assessed. Study compoundswere administered at 125 or 250 mg/kg/day (M-F) via oral gavage untilthe end of the study.

Efficacy

The efficacy of chlorambucil (2 and 3 mg/kg/d), (R-etodoalc) (400mg/kg/d) and compound 47 (250 mg/kg/d), compound 26 (250 mg/kg/d), andcompound 1 (125 mg/kg/d) against Daudi derived tumors in male SCID micewere studied. R-etodolac and compounds 1, 26 and 47 were prepared insesame oil. Both chlorambucil (ip, 0.1 ml) and compounds of theinvention (per os [p.o.], 0.31 ml) were dosed daily (Monday to Friday)for two weeks. SDX-101 (0.31 ml) was dosed p.o. daily until the end ofthe study. Slight body weight loss (<3%) was observed at the beginningof the study in chlorambucil (2 mg/kg/d), compounds 47 and 36 treatedgroups. However, all treated mice recovered after Day 2 and maintainedtheir weights. There was no body weight loss observed in other treatmentgroups. At termination of the study, the control group mean tumor volumewas 1583 mm³. The mean tumor volume of chlorambucil treated groups were864 and 766 mm³ with 2 and 3 mg/kg/d chlorambucil treatment,respectively. The mean tumor volume of R-etodolac and compounds 1, 36and 47 were 802, 996, 1011, and 1157 mm³ with compounds 47, 36, 1 andR-etodolac treatment, respectively. Analysis of variance (ANOVA) oftumor volume of control and chlorambucil groups on Day 20 showed ap-value of 0.001 and 0.0003 between the control group vs 2 and 3 mg/kg/dchlorambucil treated groups, respectively. ANOVA also showed a p-valueof 0.007 and 0.03 between the control group vs compound 47 and compoundgroups, respectively. At termination of the study, tumor samples alongwith liver, kidney, and spleen samples from each group were collectedand fixed in 10% buffered formalin for histopathology. Histologicalanalysis of all liver, spleen and kidney tissues indicated that alltissues appeared normal.

Table VII shows the time for the tumors to grow to 4× and 8× the initialvolume when mice were administered chlorambucil, R-etodolac andcompounds 1, 36 and 47. These data indicate that the compounds of theinvention inhibit tumor growth in the Daudi mouse model. TABLE VII Group4× Growth (d) 8× Growth (d) Control 8.9 14.5 Chlorambucil 16 21R-etodolac 11 17 Compound 47 16 21.5 Compound 1 15.8 21.1 Compound 3613.5 20.8

All patents and documents referenced herein are incorporated byreference.

The invention is not limited to those embodiments described herein, butmay encompass modification and variations which do not depart from thespirit of the invention. While the invention has been described inconnection with specific embodiments thereof, those of ordinary skill inthe art will understand that further modifications are within the scopeof the following claims. In addition, where features or aspects of theinvention are described in terms of Markush groups or other grouping ofalternatives, those skilled in the art will recognize that the inventionis also thereby described in terms of any individual member or subgroupof members of the Markush group or genus, and exclusions of individualmembers as appropriate.

1. A compound of Formula I:

wherein: (a) X is C, S or O; (b) R₁ is hydrogen; halogen; —OH; —SH; —CN;—NO₂; or an unsubstituted or substituted moiety selected from alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl,wherein the substituted groups are substituted with one, two or threesuitable substituents each independently selected from the groupconsisting of: halogens, —CN, —NO₂, —SH, —OH, unsubstituted alkyl,unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstitutedhaloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl,and —(CH₂)_(z)CN where z is an integer from 0 to 6; (c) R₂, R₃, R₄ andR₅ are each independently hydrogen; halogen; —OH; —SH; —CN; —NO₂; or anunsubstituted or substituted moiety selected from lower alkyl, loweralkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; (d) R₆,R₇, R₈ and R₉ are each independently hydrogen; halogen; —OH; —SH; —CN;—NO₂; or an unsubstituted or substituted moiety selected from alkyl,alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, wherein at least one of R₆, R₇, R₈ and R₉ is anunsubstituted or substituted moiety selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, alkenyl, and alkynyl; (e) R₁₀ ishydrogen; or an unsubstituted lower alkyl; (f) Y is an unsubstituted orsubstituted moiety selected from alkyl, alkenyl, and alkynyl; whereinthe substituted moiety is substituted with one, two or threesubstitutents each independently selected from halogen; —OH; —SH; —CN;—NO₂; unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls; and (g) Z is a moietyselected from —OH, —SH, —OC(O)NH₂, —SO₂H, —SO₂NH₂, —SO₂OH, —S(O)H, —NH₂,—NHC(O)H, C(O)NH₂, unsubstituted or substituted with one or two suitablesubstituents selected from the group consisting of alkyl, haloalkyl,heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl eachindependently substituted with one, two or three suitable substituents;wherein R₁ and Y may cyclize to form an unsubstituted or substitutedcycloalkyl group or an unsubstituted or substituted heterocycloalkylgroup; or a pharmaceutically acceptable prodrug, pharmaceutically activemetabolite, or pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1, wherein the substituted groups in R₂, R₃, R₄, R₅,R₆, R₇, R₈, and R₉ are substituted with one, two or three suitablesubstituents independently selected from the group consisting of:halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —NHOH, —OH, —C(O)H, —OC(O)H,—C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH₂, —NHC(NH)NH₂, —C(S)NH₂,—NHC(S)NH₂, —NHC(O)NH₂, —S(O₂)H, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O₂)H, —OS(O)H, —OSH, —SC(O)H,—S(O)C(O)OH, —SO₂C(O)OH, —NHSH, —NHS(O)H, —NHSO₂H, —C(O)SH, —C(O)S(O)H,—C(O)S(O₂)H, —C(S)H, —C(S)OH, —C(SO)OH, —C(SO₂)OH, —NHC(S)H, —OC(S)H,—OC(S)OH, —OC(SO₂)H, —S(O₂)NH₂, —S(O)NH₂, —SNH₂, —NHCS(O₂)H, —NHC(SO)H,—NHC(S)H, and —SH groups unsubstituted or substituted with one, two orthree suitable substituents each independently selected from the groupconsisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, —OR_(c), —NR_(c)OR_(c), —NR_(c)R_(c), —C(O)NR_(c),—C(O)OR_(c), —C(O)R_(c), —NR_(c)C(O)N_(c)R_(c), —NR_(c)C(O)R_(c),—OC(O)OR_(c), —OC(O)NR_(c)R_(c), —SR_(c), unsubstituted alkyls,unsubstituted haloalkyls, unsubstituted heteroalkyls, unsubstitutedalkenyls, unsubstituted alkynyls, unsubstituted aryls, unsubstitutedcycloalkyls, unsubstituted heterocycloalkyls, and unsubstitutedheteroaryls, where R_(c) is hydrogen, unsubstituted alkyl, unsubstitutedalkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl,or two or more R_(c) groups together cyclize to form part of aheteroaryl or heterocycloalkyl group unsubstituted or substituted withan unsubstituted alkyl group.
 3. A compound or pharmaceuticallyacceptable salt according to claim
 1. 4. A compound or pharmaceuticallyacceptable salt according to claim 1 wherein X is S or O.
 5. A compoundor pharmaceutically acceptable salt according to claim 1 wherein R₁ ishydrogen; or an unsubstituted moiety selected from lower alkyl, loweralkoxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, loweralkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl. 6.A compound or pharmaceutically acceptable salt according to claim 1wherein R₁ cyclizes with Y to from a substituted or unsubstitutedcycloalkyl or heterocycloalkyl group.
 7. A compound or pharmaceuticallyacceptable salt according to claim 1 wherein R₂, R₃, R₄ and R₅ are eachindependently hydrogen; or an unsubstituted moiety selected from loweralkyl, lower alkynyl, lower alkenyl, alkoxy, heteroalkyl, haloalkyl,aryl, and heteroaryl.
 8. A compound or pharmaceutically acceptable saltaccording to claim 1 wherein R₂, R₃, R₄ and R₅ are each independentlyhydrogen.
 9. A compound or pharmaceutically acceptable salt according toclaim 1 wherein R₆, R₇, R₈ and R₉ are each independently hydrogen; or anunsubstituted or substituted moiety selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl, alkoxy, allyloxy, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, wherein at least one, but not morethan two, of R₆, R₇, R₈ and R₉ is an unsubstituted or substituted moietyselected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl,and alkynyl.
 10. A compound or pharmaceutically acceptable saltaccording to claim 9, wherein the substituted moieties are eachindependently selected from the group consisting of halogen, —CN, alkyl,alkoxy, —NH₂, —O-haloalkyl, —CH(O), haloalkyl, aryl, heteroaryl,heterocycloalkyl, alkenyl, alkynyl, —OH, —C(O)₂-alkyl, and —C(O)₂H. 11.A compound or pharmaceutically acceptable salt according to claim 1,wherein R₆ is hydrogen or halogen.
 12. A compound or pharmaceuticallyacceptable salt according to claim 1, wherein R₇ is hydrogen; halogen;or an unsubstituted or substituted moiety selected from aryl,heteroaryl, alkyl, heterocycloalkyl, and alkoxy, wherein the substitutedmoiety is substituted with one, two or three substituents independentlyselected from the group consisting of —OH, —C(O)₂-alkyl, —C(O)₂H,alkoxy, —O-haloalkyl, halogen, alkyl, haloalkyl, and —NH₂.
 13. Acompound or pharmaceutically acceptable salt according to claim 1,wherein R₈ is hydrogen or halogen.
 14. A compound or pharmaceuticallyacceptable salt according to claim 1, wherein R₉ is hydrogen; halogen;or an unsubstituted or substituted moiety selected from alkyl, aryl,heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl, andhaloalkyl, wherein the substituted moiety is substituted with one, twoor three substitutents independently selected from the group consistingof alkyl, —C(O)H, —CN, halogen, alkoxy, aryl, and —C(O)₂H. 15.(canceled)
 16. A compound or pharmaceutically acceptable salt accordingto claim 1, wherein X is O.
 17. A compound or pharmaceuticallyacceptable salt according to claim 1, wherein Y is lower alkyl.
 18. Acompound or pharmaceutically acceptable salt according to claim 1,wherein Z is hydroxy.
 19. A compound or pharmaceutically acceptable saltaccording to claim 1, wherein Z is —(C)(O)NH₂ unsubstituted orsubstituted with one or two alkyl groups.
 20. A compound orpharmaceutically acceptable salt according to claim 1, wherein Z ishydroxyl, unsubstituted or substituted lower alkoxy, amino, loweralkylamino, di(lower)alkylamino, arylamino, (aryl)lower alkylamino,di(aryl)lower alkylamino, di(aryl)amino, (heterocycle)amino,(heterocycle)lower alkylamino, di(heterocycle)lower alkylamino, anddi(heterocycles)amino.
 21. A compound or pharmaceutically acceptablesalt according to claim 1, wherein the substituted groups in R₂, R₃, R₄,R₅, R₆, R₇, R₈, and R₉ are substituted with one, two or three suitablesubstituents each independently selected from the group consisting of:halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH,—OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of halogens, ═O, —OH, —SH, —NO₂, —CN,—(CH₂)_(z)—CN where z is an integer from 0 to 6, unsubstituted alkyls,unsubstituted haloalkyls, unsubstituted heteroalkyls, unsubstitutedalkenyls, unsubstituted alkynyls, unsubstituted aryls, unsubstitutedcycloalkyls, unsubstituted heterocycloalkyls, and unsubstitutedheteroaryls.
 22. A compound or pharmaceutically acceptable saltaccording to claim 1 wherein: (a) X is S or O; (b) R₁ is hydrogen; or anunsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy,lower alkenyl; lower alkenyl-hydroxy, lower alkynyl, loweralkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; (c)R₂, R₃, R₄ and R₅ are each independently hydrogen; or an unsubstitutedmoiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy,haloalkyl, aryl, and heteroaryl; (d) R₆, R₇, R₈ and R₉ are eachindependently hydrogen; or an unsubstituted or substituted moietyselected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substitutedmoieties are each independently selected from the group consisting ofhalogen, —CN, alkyl, alkoxy, —NH₂, —O-haloalkyl, —CH(O), haloalkyl,aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, —OH, —C(O)₂-alkyl,and —C(O)₂H; and (e) R₁₀ is hydrogen.
 23. A compound or pharmaceuticallyacceptable salt according to claim 1 wherein (a) X is O; (b) R₁ is anunsubstituted alkyl group or unsubstituted aryl group; (c) R₂, R₃, R₄and R₅ are each hydrogen; (d) R₇ is an unsubstituted or substitutedmoiety selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl;and (e) R₁₀ is hydrogen.
 24. A compound or pharmaceutically acceptablesalt according to claim 1 wherein: (a) R₉ is an unsubstituted alkylgroup; (b) Y is an unsubstituted alkyl group; and (c) Z is hydroxyl. 25.A compound or pharmaceutical salt according to claim 1, wherein at leastone of R₆, R₇, R₈ and R₉ is an aryl group unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl,alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is an integer from 0to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂,—NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH,—C(S)H, and —SH groups unsubstituted or substituted with one, two orthree suitable substituents each independently selected from the groupconsisting of halogens, ═O, —NO₂, —OH, —SH, —CN, —(CH₂)_(z)—CN where zis an integer from 0 to 6, unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
 26. Acompound or pharmaceutical salt according to claim 1, wherein at leastone of R₆, R₇, R₈ and R₉ is a heteroaryl group unsubstituted orsubstituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 27. A compound orpharmaceutical salt according to claim 1, wherein at least one of R₆,R₇, R₈ and R₉ is a heterocycloalkyl group unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl,alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is an integer from 0to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂,—NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH,—C(S)H, and —SH groups unsubstituted or substituted with one, two orthree suitable substituents each independently selected from the groupconsisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 28. A compound orpharmaceutically acceptable salt according to claim 1 wherein: (a) X isO or S; (b) R₁ is an unsubstituted lower alkyl group or unsubstitutedaryl group; (c) R₂, R₃, R₄ and R₅ are each hydrogen; (d) R₆ is hydrogenor halogen; (e) R₇ is an unsubstituted or substituted moiety selectedfrom alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl; (f) R₈ is hydrogen or halogen; (g) R₉ is anunsubstituted or substituted moiety selected from alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R₁₀ ishydrogen.
 29. A compound or pharmaceutically acceptable salt accordingto claim 28 wherein Y is an unsubstituted lower alkyl group and Z ishydroxyl.
 30. A compound or pharmaceutically acceptable salt accordingto claim 1, wherein at least one of R₇ or R₉ is an aryl groupunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting of:halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CNwhere z is an integer from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH,—OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂,—NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substitutedwith one, two or three suitable substituents each independently selectedfrom the group consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CNwhere z is an integer from 0 to 6, unsubstituted alkyls, unsubstitutedhaloalkyls, unsubstituted heteroalkyls, unsubstituted alkenyls,unsubstituted alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
 31. Acompound or pharmaceutically acceptable salt according to claim 1,wherein at least one of R₇ or R₉ is an heteroaryl group unsubstituted orsubstituted with one, two or three suitable substituents eachindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 32. A compound orpharmaceutically acceptable salt according to claim 1, wherein at leastone of R₇ or R₉ is an alkenyl group unsubstituted or substituted withone, two or three suitable substituents each independently selected fromthe group consisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl,heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, —(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH,—C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 33. A compound orpharmaceutically acceptable salt according to claim 1, wherein at leastone of R₇ or R₉ is an alkynyl group unsubstituted or substituted withone, two or three suitable substituents each independently selected fromthe group consisting of: halogens, ═O, ═S, —CN, —NO₂, alkyl, alkenyl,heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, —(CH₂)_(z)CN where z is an integer from 0 to 6, ═NH, —OH,—C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂,—C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(S)H, and —SH groupsunsubstituted or substituted with one, two or three suitablesubstituents each independently selected from the group consisting ofhalogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is an integer from 0 to6, unsubstituted alkyls, unsubstituted haloalkyls, unsubstitutedheteroalkyls, unsubstituted alkenyls, unsubstituted alkynyls,unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 34. A compound orpharmaceutically acceptable salt according to claim 1 wherein: (a) X isO; (b) R₁ is an unsubstituted moiety selected from aryl, alkyl, andlower-alkoxy; (c) R₂, R₃, R₄, and R₅ are each hydrogen; (d) R₆ and R₈are each hydrogen or halogen; R₇ is an unsubstituted or substituted arylgroup or an unsubstituted or substituted heteroaryl group; R₉ isselected from halogen; unsubstituted alkyl; and an unsubstituted orsubstituted moiety selected from aryl, heteroaryl, cycloalkyl, alkenyl,and alkynyl; and (e) R₁₀ is hydrogen; wherein the substituted groups inR₇ and R₉ are substituted with one, two or three suitable substituentsindependently selected from the group consisting of: halogens, ═O, ═S,—CN, —NO₂, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is aninteger from 0 to 6, ═NH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,—C(NH)NH₂, —NHC(O)NH₂, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H,—NHC(O)OH, —C(S)H, and —SH groups unsubstituted or substituted with one,two or three suitable substituents each independently selected from thegroup consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is aninteger from 0 to 6, unsubstituted alkyls, unsubstituted haloalkyls,unsubstituted heteroalkyls, unsubstituted alkenyls, unsubstitutedalkynyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstitutedheterocycloalkyls, and unsubstituted heteroaryls.
 35. A compound orpharmaceutically acceptable salt according to claim 34 wherein: (a) Y isan unsubstituted lower alkyl group; and (b) Z is hydroxyl.
 36. Acompound selected from the group consisting of:

pharmaceutically acceptable salt thereof.
 37. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticalcomposition comprising a therapeutically effective amount of an agentselected from the group consisting of compounds and salts as defined inclaim 1 and a pharmaceutically acceptable carrier.
 39. A pharmaceuticalcomposition comprising a therapeutically effective amount of an agentselected from the group consisting of compounds and salts as defined inclaim 36 and a pharmaceutically acceptable carrier.
 40. A method oftreating a neoplasia comprising administering to a subject in needthereof a therapeutically effective amount of a composition comprising acompound of claim
 1. 41. A method according to claim 40 wherein theneoplasia is a hematological cancer.
 42. A method according to claim 41wherein the neoplasia is selected from leukemias, myelomas andlymphomas.
 43. A method according to claim 40, wherein the neoplasia isselected from brain cancer, bone cancer, basal cell carcinoma,adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer,esophageal cancer, small bowel cancer, stomach cancer, colon cancer,liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervicalcancer, lung cancer, breast cancer, skin cancer, prostate cancer, andrenal cell carcinoma.
 44. A method according to claim 40, wherein thecompound is given in combination with another antineoplastic agent. 45.A method according to claim 44, wherein the antineoplastic agent is analkylating agent.
 46. A method according to claim 45, wherein thealkylating agent is selected from the group consisting of bendamustine,chlorambucil, cyclophosphamide and melphalan.
 47. A method according toclaim 46, wherein the alkylating agent is bendamustine.
 48. A methodaccording to 44, wherein the antineoplastic agent is a glucocorticoid.49. A method according to 48, wherein the glucocoritcoid is prednisone.50. A method according to claim 48, wherein the glucocorticoid is givenin combination with additional antineoplastic agents.
 51. A method ofreducing or preventing the development of Alzheimer's disease comprisingadministering to a subject in thereof a therapeutically effective amountof a composition comprising a compound of claim
 1. 52. A method oftreating Alzheimer's disease in a mammal comprising administering to amammal in need of such treatment a therapeutically effective amount of:(a) at least one compound, pharmaceutically acceptable salt,pharmaceutically acceptable prodrug, or pharmaceutically activemetabolite defined in claim 1; and (b) at least one agent selected fromthe group consisting of estrogen, risperidone, a thiobenzodiazepine,ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide,DM9384, a cholinesterase inhibitor, donepezil hydrochloride,rivastigmine tartrate, galantamine, NGF, and metrifonate.
 53. A methodof treatment of a disease in a mammal treatable by administration of aCOX-1 and/or COX-2 inhibitor comprising administering to the mammal atherapeutically effective amount of a compound of claim 1 which inhibitsone or both of COX-1 or COX-2.
 54. A method according to claim 53wherein the disease is an inflammatory disease.
 55. A method oftreatment of a hyperplastic disease in a mammal comprisingadministration to the mammal a therapeutically effective amount of acompound of claim
 1. 56. A method of inhibiting or delaying the onset ofa neoplasia in a mammal in need of such treatment comprisingadministration to the mammal a therapeutically effective amount of acompound of claim
 1. 57. A method according to claim 56 wherein saidneoplasia is selected from the group consisting of adenomatous polyps,gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer,prostate cancer, lung cancer, breast cancer, and skin cancer.
 58. Amethod for treating, inhibiting or delaying the onset of uncontrolled orabnormal angiogenesis in a subject in need of such treatment, inhibitionor delay, wherein the uncontrolled or abnormal angiogenesis is selectedfrom the group consisting of metastasis, corneal graft rejection, ocularneovascularization, retinal neovascularization, diabetic retinopathy,retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantilehemaginomas, angiofibroma of the nasopharynx, avascular necrosis ofbone, and endometriosis, and the method comprises treating the subjectwith a therapeutically effective amount of a compound of claim
 1. 59. Apharmaceutical composition for the treatment of a condition selectedfrom the group consisting of arthritis, fever, common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer, tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis, aorticaneurysm, periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neuro-degenerative disorders, autoimmune disorders,Huntington's disease, Parkinson's disease, migraine, depression,peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders, myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases, sepsis, premature labor, hypoprothrombinemia, hemophilia,thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity,schizophrenia, kidney disease, Rickettsial infections, Protozoandiseases, reproductive disorders, obesity, and septic shock in a mammal,comprising an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof effective in such treatmentsand a pharmaceutically acceptable carrier.
 60. A method for treating acondition selected from the group consisting of arthritis, fever, commoncold, dysmenorrhea, menstrual cramps, inflammatory bowel disease,Crohn's disease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer, tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,loosening of artificial joint implants, atherosclerosis, aorticaneurysm, periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neuro-degenerative disorders, autoimmune disorders,Huntington's disease, Parkinson's disease, migraine, depression,peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders, myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases, sepsis, premature labor, hypoprothrombinemia, hemophilia,thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity,schizophrenia, kidney disease, Rickettsial infections, Protozoandiseases, myelodymyelodysplastic syndrome, reproductive disorders,obesity, and septic shock in a mammal, comprising administering to saidmammal a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt thereof effective intreating such a condition.
 61. A method of treating a disease mediatedby PPAR in a mammal by administering to a mammal in need of suchtreatment a therapeutically effective amount of at least one compound,pharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite as defined in claim 1.